74 results on '"Nicolas Blondeau"'
Search Results
2. Unlocking Therapeutic Synergy: Tailoring Drugs for Comorbidities such as Depression and Diabetes through Identical Molecular Targets in Different Cell Types
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Thierry Coppola, Guillaume Daziano, Ilona Legroux, Sophie Béraud-Dufour, Nicolas Blondeau, and Patricia Lebrun
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depression ,diabetes ,pharmacology ,cell signaling ,receptor ,channel ,Cytology ,QH573-671 - Abstract
Research in the field of pharmacology aims to generate new treatments for pathologies. Nowadays, there are an increased number of chronic disorders that severely and durably handicap many patients. Among the most widespread pathologies, obesity, which is often associated with diabetes, is constantly increasing in incidence, and in parallel, neurodegenerative and mood disorders are increasingly affecting many people. For years, these pathologies have been so frequently observed in the population in a concomitant way that they are considered as comorbidities. In fact, common mechanisms are certainly at work in the etiology of these pathologies. The main purpose of this review is to show the value of anticipating the effect of baseline treatment of a condition on its comorbidity in order to obtain concomitant positive actions. One of the implications would be that by understanding and targeting shared molecular mechanisms underlying these conditions, it may be possible to tailor drugs that address both simultaneously. To this end, we firstly remind readers of the close link existing between depression and diabetes and secondly address the potential benefit of the pleiotropic actions of two major active molecules used to treat central and peripheral disorders, first a serotonin reuptake inhibitor (Prozac ®) and then GLP-1R agonists. In the second part, by discussing the therapeutic potential of new experimental antidepressant molecules, we will support the concept that a better understanding of the intracellular signaling pathways targeted by pharmacological agents could lead to future synergistic treatments targeting solely positive effects for comorbidities.
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- 2023
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3. The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles
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Michel Tauc, Marc Cougnon, Romain Carcy, Nicolas Melis, Thierry Hauet, Luc Pellerin, Nicolas Blondeau, and Didier F. Pisani
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Biotechnology ,TP248.13-248.65 ,Biology (General) ,QH301-705.5 ,Biochemistry ,QD415-436 - Abstract
Abstract Since the demonstration of its involvement in cell proliferation, the eukaryotic initiation factor 5A (eIF5A) has been studied principally in relation to the development and progression of cancers in which the isoform A2 is mainly expressed. However, an increasing number of studies report that the isoform A1, which is ubiquitously expressed in normal cells, exhibits novel molecular features that reveal its new relationships between cellular functions and organ homeostasis. At a first glance, eIF5A can be regarded, among other things, as a factor implicated in the initiation of translation. Nevertheless, at least three specificities: (1) its extreme conservation between species, including plants, throughout evolution, (2) its very special and unique post-translational modification through the activating-hypusination process, and finally (3) its close relationship with the polyamine pathway, suggest that the role of eIF5A in living beings remains to be uncovered. In fact, and beyond its involvement in facilitating the translation of proteins containing polyproline residues, eIF5A is implicated in various physiological processes including ischemic tolerance, metabolic adaptation, aging, development, and immune cell differentiation. These newly discovered physiological properties open up huge opportunities in the clinic for pathologies such as, for example, the ones in which the oxygen supply is disrupted. In this latter case, organ transplantation, myocardial infarction or stroke are concerned, and the current literature defines eIF5A as a new drug target with a high level of potential benefit for patients with these diseases or injuries. Moreover, the recent use of genomic and transcriptomic association along with metadata studies also revealed the implication of eIF5A in genetic diseases. Thus, this review provides an overview of eIF5A from its molecular mechanism of action to its physiological roles and the clinical possibilities that have been recently reported in the literature.
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- 2021
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4. Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney
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Marc Cougnon, Romain Carcy, Nicolas Melis, Isabelle Rubera, Christophe Duranton, Karine Dumas, Jean-François Tanti, Catherine Pons, Nicolas Soubeiran, Marina Shkreli, Thierry Hauet, Luc Pellerin, Sébastien Giraud, Nicolas Blondeau, Michel Tauc, and Didier F. Pisani
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Cytology ,QH573-671 - Abstract
Abstract Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux. At the same time, GC7 modifies the native energy source of the proximal cells from glutamine toward glucose use. Thus, GC7 acutely and reversibly reprogrammes function and metabolism of kidney cells to make glucose its single substrate, and thus allowing cells to be oxygen independent through anaerobic glycolysis. The physiological consequences are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis. Such a reversible reprogramming of glucose handling and oxygen dependence of kidney cells by GC7 represents a pharmacological opportunity in ischaemic as well as hyperglycaemia-associated pathologies from renal origin.
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- 2021
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5. Tackling issues in the path toward clinical translation in brain conditioning: Potential offered by nutraceuticals
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Joseph S Tauskela, Miled Bourourou, and Nicolas Blondeau
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brain ischemia ,ischemic conditioning ,neuroprotection ,nutraceutical ,stroke ,Medical technology ,R855-855.5 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Brief periods of ischemia have been shown in many experimental setups to provide tolerance against ischemia in multiple organs including the brain, when administered before (preconditioning) or even after (postconditioning) the normally lethal ischemia. In addition to these so-called ischemic conditionings, many pharmacological and natural agents (e.g., chemicals and nutraceuticals) can also act as potent pre- and post-conditioners. Deriving from the original concept of ischemic preconditioning, these various conditioning paradigms may be promising as clinical-stage therapies for prevention of ischemic-related injury, especially stroke. As no proven experimentally identified strategy has translated into clinical success, the experimental induction of neuroprotection using these various conditioning paradigms has raised several questions, even before considering translation to clinical studies in humans. The first aim of the review is to consider key questions on preclinical studies of pre- or post-conditioning modalities including those induced by chemical or nutraceuticals. Second, we make the argument that several key issues can be addressed by a novel concept, nutraceutical preconditioning. Specifically, α-linolenic acid (alpha-linolenic acid [ALA] an omega-3 polyunsaturated fatty acid), contained in plant-derived edible products, is essential in the daily diet, and a body of work has identified ALA as a pre- and post-conditioner of the brain. Nutritional intervention and functional food development are an emerging direction for preventing stroke damage, offering the potential to improving clinical outcomes through activation of the endogenous protective mechanisms known collectively as conditioning.
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- 2017
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6. Sortilin in Glucose Homeostasis: From Accessory Protein to Key Player?
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Nicolas Blondeau, Sophie Béraud-Dufour, Patricia Lebrun, Céline Hivelin, and Thierry Coppola
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diabetes ,receptor ,pharmacology ,signaling ,physiology ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The pharmacological properties and physiological roles of the type I receptor sortilin, also called neurotensin receptor-3, are various and complex. Sortilin is involved in important biological functions from neurotensin and pro-Nerve Growth Factor signaling in the central nervous system to regulation of glucose and lipid homeostasis in the periphery. The peripheral functions of sortilin being less extensively addressed, the focus of the current review is to discuss recent works describing sortilin-induced molecular mechanisms regulating blood glucose homeostasis and insulin signaling. Thus, an overview of several roles ascribed to sortilin in diabetes and other metabolic diseases are presented. Investigations on crucial cellular pathways involved in the protective effect of sortilin receptor on beta cells, including recent discoveries about regulation of cell fate, are also detailed. In addition, we provide a special focus on insulin secretion regulation involving complexes between sortilin and neurotensin receptors. The last section comments on the future research areas which should be developed to address the function of new effectors of the sortilin system in the endocrine apparatus.
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- 2019
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7. Ionic Homeostasis Maintenance in ALS: Focus on New Therapeutic Targets
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Rossana Sirabella, Valeria Valsecchi, Serenella Anzilotti, Ornella Cuomo, Antonio Vinciguerra, Pasquale Cepparulo, Paola Brancaccio, Natascia Guida, Nicolas Blondeau, Lorella M. T. Canzoniero, Cristina Franco, Salvatore Amoroso, Lucio Annunziato, and Giuseppe Pignataro
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ionic homeostasis ,ALS ,neurodegeneration ,transporters ,channels ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Amyotrophic lateral sclerosis (ALS) is one of the most threatening neurodegenerative disease since it causes muscular paralysis for the loss of Motor Neurons in the spinal cord, brainstem and motor cortex. Up until now, no effective pharmacological treatment is available. Two forms of ALS have been described so far: 90% of the cases presents the sporadic form (sALS) whereas the remaining 10% of the cases displays the familiar form (fALS). Approximately 20% of fALS is associated with inherited mutations in the Cu, Zn-superoxide dismutase 1 (SOD1) gene. In the last decade, ionic homeostasis dysregulation has been proposed as the main trigger of the pathological cascade that brings to motor-neurons loss. In the light of these premises, the present review will analyze the involvement in ALS pathophysiology of the most well studied metal ions, i.e., calcium, sodium, iron, copper and zinc, with particular focus to the role of ionic channels and transporters able to contribute in the regulation of ionic homeostasis, in order to propose new putative molecular targets for future therapeutic strategies to ameliorate the progression of this devastating neurodegenerative disease.
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- 2018
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8. Hypothalamic Inflammation and Energy Balance Disruptions: Spotlight on Chemokines
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Ophélia Le Thuc, Katharina Stobbe, Céline Cansell, Jean-Louis Nahon, Nicolas Blondeau, and Carole Rovère
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neuroinflammation ,hypothalamus ,chemokines ,energy balance ,metabolic diseases ,high-fat diet ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
The hypothalamus is a key brain region in the regulation of energy balance as it controls food intake and both energy storage and expenditure through integration of humoral, neural, and nutrient-related signals and cues. Many years of research have focused on the regulation of energy balance by hypothalamic neurons, but the most recent findings suggest that neurons and glial cells, such as microglia and astrocytes, in the hypothalamus actually orchestrate together several metabolic functions. Because glial cells have been described as mediators of inflammatory processes in the brain, the existence of a causal link between hypothalamic inflammation and the deregulations of feeding behavior, leading to involuntary weight loss or obesity for example, has been suggested. Several inflammatory pathways that could impair the hypothalamic control of energy balance have been studied over the years such as, among others, toll-like receptors and canonical cytokines. Yet, less studied so far, chemokines also represent interesting candidates that could link the aforementioned pathways and the activity of hypothalamic neurons. Indeed, chemokines, in addition to their role in attracting immune cells to the inflamed site, have been suggested to be capable of neuromodulation. Thus, they could disrupt cellular activity together with synthesis and/or secretion of multiple neurotransmitters/mediators involved in the maintenance of energy balance. This review discusses the different inflammatory pathways that have been identified so far in the hypothalamus in the context of feeding behavior and body weight control impairments, with a particular focus on chemokines signaling that opens a new avenue in the understanding of the major role played by inflammation in obesity.
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- 2017
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9. Requirement for preclinical prioritization of neuroprotective strategies in stroke: Incorporation of preconditioning
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S., Tauskela Joseph and Nicolas, Blondeau
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Quantitative Biology - Tissues and Organs - Abstract
Acute neuroprotection in numerous human clinical trials has been an abject failure. Major systemic-and procedural-based issues have subsequently been identified in both clinical trials and preclinical animal model experimentation. As well, issues related to the neuroprotective moiety itself have contributed to clinical trial failures, including late delivery, mono-targeting, low potency and poor tolerability. Conditioning (pre-or post-) strategies can potentially address these issues and are therefore gaining increasing attention as approaches to protect the brain from cerebral ischemia. In principle, conditioning can address concerns of timing (preconditioning could be pre-emptively applied in high-risk patients, and post-conditioning after patients experience an unannounced brain infarction) and signaling (multi-modal). However, acute neuroprotection and conditioning strategies face a common translational issue: a myriad of possibilities exist, but with no strategy to select optimal candidates. In this review, we argue that what is required is a neuroprotective framework to identify the "best" agent(s), at the earliest investigational stage possible. This may require switching mindsets from identifying how neuroprotection can be achieved to determining how neuroprotection can fail, for the vast majority of candidates. Understanding the basis for failure can in turn guide supplementary treatment, thereby forming an evidence-based rationale for selecting combinations of therapies. An appropriately designed in vitro (neuron culture, brain slices) approach, based on increasing the harshness of the ischemic-like insult, can be useful in identifying the "best" conditioner or acute neuroprotective therapy, as well as how the two modalities can be combined to overcome individual limitations. This would serve as a base from which to launch further investigation into therapies required to protect the neurovascular unit in in vivo animal models of cerebral ischemia. Based on these respective approaches, our laboratories suggest that there is merit in examining synaptic activity-and nutraceutical-based preconditioning / acute neuroprotection.
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- 2019
10. Dictionnaire érotique Latin-Français
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Nicolas Blondeau, François Noel and Nicolas Blondeau, François Noel
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- 2018
11. Combattre l’accident vasculaire cérébral en inhibant une enzyme liée à la voie de synthèse des polyamines
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Nicolas Blondeau, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
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chemistry.chemical_classification ,0303 health sciences ,business.industry ,[SDV]Life Sciences [q-bio] ,Polyamine synthesis ,General Medicine ,Pharmacology ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Enzyme ,chemistry ,Medicine ,business ,Stroke ,ComputingMilieux_MISCELLANEOUS ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
International audience; No abstract available
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- 2021
12. Linotrins: Omega-3 oxylipins featuring an E,Z,E conjugated triene motif are present in the plant kingdom and alleviate inflammation in LPS-challenged microglial cells
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Laurence Balas, Sujit Kumar Dey, Sophie Béraud-Dufour, Dean Edward Riechers, Olivia Augusta Landau, Justine Bertrand-Michel, Thierry Durand, Nicolas Blondeau, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), University of Illinois [Chicago] (UIC), University of Illinois System, Plateau MetaToul-LIPIDOMIQUE = MetaToul-Lipidomics, MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Pharmacology ,Inflammation ,Lipopolysaccharides ,Linolenic acid ,[SDV]Life Sciences [q-bio] ,Organic Chemistry ,alpha-Linolenic Acid ,Total synthesis ,General Medicine ,Conjugated triene ,Drug Discovery ,Humans ,Microglial cell ,Microglia ,Oxylipins ,Cytokine - Abstract
International audience; Alpha-linolenic acid (ALA), an essential omega-3 polyunsaturated fatty acid found in plants, exertsneuroprotection and anti-inflammatory effects in chronic and acute CNS disease models. However, theunderlying mechanisms are not yet understood. Since ALA is not incorporated into the brain, theobserved health benefits may result from some of its metabolites. The putative formation of dihydroxylatedALA derivatives (called linotrins) was recently shown in vitro in the presence of lipoxygenases.However, the in vitro biosynthesis of linotrins was neither stereoselective nor quantitatively efficient forstudying their physiological roles as enantiomeric pure forms. Herein, we report the first stereocontrolledsynthesis that features regio- and stereoselective hydrometalations of alkynes for assemblingthe sensitive E,Z,E-conjugated trienes, as well as LC-MS investigations that provide evidence oflinotrins occurrence in plants. Moreover, strong anti-inflammatory effects on microglia highlight thepotential physiological importance of linotrins and open new perspectives in search of CNS therapeutics.
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- 2021
13. [Fighting stroke by inhibiting an enzyme linked to the polyamine synthesis pathway]
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Nicolas, Blondeau
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Stroke ,Polyamines ,Humans ,Biosynthetic Pathways - Published
- 2021
14. Targeting oxidative stress, a crucial challenge in renal transplantation outcome
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Michel Tauc, Laurent Counillon, Antoine Sicard, Romain Carcy, Thierry Hauet, Didier F. Pisani, Manon Durandy, Marc Cougnon, Mallorie Poët, Nicolas Blondeau, Pisani, Didier, Laboratoire de PhysioMédecine Moléculaire (LP2M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de pharmacologie moléculaire et cellulaire (IPMC), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
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0301 basic medicine ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Ischemia ,Bioinformatics ,medicine.disease_cause ,Biochemistry ,Organ transplantation ,Antioxidants ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,medicine ,Humans ,Stroke ,ComputingMilieux_MISCELLANEOUS ,Kidney ,business.industry ,Acute kidney injury ,Hypoxia (medical) ,medicine.disease ,Kidney Transplantation ,3. Good health ,Transplantation ,[SDV] Life Sciences [q-bio] ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,Reperfusion Injury ,medicine.symptom ,business ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Disorders characterized by ischemia/reperfusion (I/R) are the most common causes of debilitating diseases and death in stroke, cardiovascular ischemia, acute kidney injury or organ transplantation. In the latter example the I/R step defines both the amplitude of the damages to the graft and the functional recovery outcome. During transplantation the kidney is subjected to blood flow arrest followed by a sudden increase in oxygen supply at the time of reperfusion. This essential clinical protocol causes massive oxidative stress which is at the basis of cell death and tissue damage. The involvement of both reactive oxygen species (ROS) and nitric oxides (NO) has been shown to be a major cause of these cellular damages. In fact, in non-physiological situations, these species escape endogenous antioxidant control and dangerously accumulate in cells. In recent years, the objective has been to find clinical and pharmacological treatments to reduce or prevent the appearance of oxidative stress in ischemic pathologies. This is very relevant because, due to the increasing success of organ transplantation, clinicians are required to use limit organs, the preservation of which against oxidative stress is crucial for a better outcome. This review highlights the key actors in oxidative stress which could represent new pharmacological targets.
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- 2021
15. Therapeutic potential of prenylated stilbenoid macasiamenene F through its anti-inflammatory and cytoprotective effects on LPS-challenged monocytes and microglia
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Vilailak Prachyawarakorn, Veronika Leláková, Catherine Heurteaux, Phanruethai Pailee, Nicolas Blondeau, Jean Mazella, Sophie Béraud-Dufour, Jiří Václavík, Jan Hošek, Catherine Widmann, Karel Šmejkal, Thierry Coppola, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Czech Technical University in Prague (CTU), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Université Côte d'Azur (UCA)
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Lipopolysaccharides ,Male ,Lipopolysaccharide ,[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Anti-Inflammatory Agents ,microglia ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Pharmacology ,Stilbenoid ,neuroinflammation ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Drug Discovery ,Stilbenes ,natural stilbenoids ,Cells, Cultured ,0303 health sciences ,Microglia ,Euphorbiaceae ,prenyl ,3. Good health ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,medicine.symptom ,Inflammation Mediators ,monocytes ,medicine.drug_class ,Inflammation ,Biology ,Anti-inflammatory ,03 medical and health sciences ,In vivo ,Cell Line, Tumor ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Humans ,Neuroinflammation ,030304 developmental biology ,Prenylation ,Dose-Response Relationship, Drug ,Plant Extracts ,Monocyte ,[SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy ,Mice, Inbred C57BL ,chemistry ,Cytoprotection ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition - Abstract
Ethnopharmacological relevance Macaranga Thou. (Euphorbiaceae) is a large genus that comprises over 300 species distributed between Western Africa and the islands of the South Pacific. Plants of this genus have a long-standing history of use in traditional medicine for different purposes, including the treatment of inflammation. Fresh and dried leaves of certain Macaranga species (e.g. M. tanarius (L.) Mull.Arg.), have been used to treat cuts, bruises, boils, swellings, sores and covering of wounds in general. Several reports described Macaranga spp. being a rich source of polyphenols, such as prenylated stilbenoids and flavonoids, mostly responsible for its biological activity. Similarly, an abundant content of prenylated stilbenes was also described in M. siamensis S.J.Davies, species recently identified (2001) in Thailand. While the respective biological activity of the prenylated stilbenes from M. siamensis was poorly investigated to date, our recent study pointed out the interest as the natural source of several novel anti-inflammatory stilbenoids isolated from this species. Aim of the study This work investigated the potential anti-inflammatory effects of the stilbenoid macasiamenene F (MF) isolated from M. siamensis S.J.Davies (Euphorbiaceae) on the lipopolysaccharide (LPS)-induced inflammation-like response of monocytes and microglia, major cells involved in the peripheral and central inflammatory response, respectively. Materials and methods LPS-induced stimulation of TLR4 signaling led to the activation of inflammatory pathways in in vitro models of THP-1 and THP-1-XBlue™-MD2-CD14 human monocytes, BV-2 mouse microglia, and an ex vivo model of brain-sorted mouse microglia. The ability of the stilbenoid MF to intervene in the IкB/NF-кB and MAPKs/AP-1 inflammatory cascade was investigated. The gene and protein expressions of the pro-inflammatory cytokines IL-1β and TNF-α were evaluated at the transcription and translation levels. The protective effect of MF against LPS-triggered microglial loss was assessed by cell counting and the LDH assay. Results MF demonstrated beneficial effects, reducing both monocyte and microglial inflammation as assessed in vitro. It efficiently inhibited the degradation of IкBα, thereby reducing the NF-кB activity and TNF-α expression in human monocytes. Furthermore, the LPS-induced expression of IL-1β and TNF-α in microglia was dampened by pre-, co-, or post-treatment with MF. In addition to its anti-inflammatory effect, MF demonstrated a cytoprotective effect against the LPS-induced death of BV-2 microglia. Conclusion Our research into anti-inflammatory and protective effects of MF has shown that it is a promising candidate for further in vitro and in vivo investigations of MF interventions with respect to acute and chronic inflammation, including potentially beneficial effects on the inflammatory component of brain diseases such as stroke and Alzheimer's disease.
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- 2020
16. Inhibition of eIF5A hypusination pathway as a new pharmacological target for stroke therapy
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Miled Bourourou, Michel Tauc, Jonas Friard, Nicolas Melis, Elsa Gouix, Catherine Heurteaux, Nicolas Blondeau, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Laboratoire de PhysioMédecine Moléculaire (LP2M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Physiologie cellulaire et moléculaire des systèmes intégrés (PCMSI), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
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Male ,[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Mitochondrion ,Brain ischemia ,Mice ,0302 clinical medicine ,Cognition ,Peptide Initiation Factors ,polyamine ,Eukaryotic initiation factor ,Polyamines ,Translation factor ,Stroke ,0303 health sciences ,Oxidoreductases Acting on CH-NH Group Donors ,Behavior, Animal ,RNA-Binding Proteins ,Translation (biology) ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,Neuroprotection ,3. Good health ,mitochondria ,Neurology ,Ischemic Attack, Transient ,Models, Animal ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Cardiology and Cardiovascular Medicine ,EIF5A ,Injections, Intraperitoneal ,Guanine ,Ischemia ,03 medical and health sciences ,[SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication ,medicine ,Animals ,eIF5A ,030304 developmental biology ,business.industry ,oxidative stress neuroprotection ,Lysine ,Original Articles ,medicine.disease ,Mice, Inbred C57BL ,Oxidative Stress ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Neurology (clinical) ,business ,Reactive Oxygen Species ,Neuroscience ,030217 neurology & neurosurgery - Abstract
International audience; In eukaryotes, the polyamine pathway generates spermidine that activates the hypusination of the translation factor eukaryotic initiation factor 5A (eIF5A). Hypusinated-eIF5A modulates translation, elongation, termination and mitochondrial function. Evidence in model organisms like drosophila suggests that targeting polyamines synthesis might be of interest against ischemia. However, the potential of targeting eIF5A hypusination in stroke, the major therapeutic challenge specific to ischemia, is currently unknown. Using in vitro models of ischemic-related stress, we documented that GC7, a specific inhibitor of a key enzyme in the eIF5A activation pathway, affords neuronal protection. We identified the preservation of mitochondrial function and thereby the prevention of toxic ROS generation as major processes of GC7 protection. To represent a thoughtful opportunity of clinical translation, we explored whether GC7 administration reduces the infarct volume and functional deficits in an in vivo transient focal cerebral ischemia (tFCI) model in mice. A single GC7 pre- or post-treatment significantly reduces the infarct volume post-stroke. Moreover, GC7-post-treatment significantly improves mouse performance in the rotarod and Morris water-maze, highlighting beneficial effects on motor and cognitive post-stroke deficits. Our results identify the targeting of the polyamine-eIF5A-hypusine axis as a new therapeutic opportunity and new paradigm of research in stroke and ischemic diseases.
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- 2020
17. Fat food exacerbates post-prandial hypothalamic inflammation involving GFAP+ cells and microglia
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Nicolas Blondeau, Frédéric Brau, S. Ben-Fradj, Etienne Audinat, J. Leredde, O. Le Thuc, Alexandre Benani, Jean-Louis Nahon, Nadège Devaux, Katharina Stobbe, Cynthia Lebeaupin, Céline Cansell, Lucile Fleuriot, Carole Rovère, Delphine Debayle, and Coralie-Anne Mosser
- Subjects
0303 health sciences ,medicine.medical_specialty ,Cell type ,Microglia ,digestive, oral, and skin physiology ,Inflammation ,Biology ,medicine.disease ,Obesity ,Glial cell proliferation ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,medicine.anatomical_structure ,Hypothalamus ,Internal medicine ,Gene expression ,medicine ,medicine.symptom ,030217 neurology & neurosurgery ,030304 developmental biology ,Astrocyte - Abstract
In humans, obesity was associated with brain inflammation and glial cell proliferation. Studies in rodents showed that glial cell proliferation occurs within 24 hours of high-fat diet (HFD) consumption, before obesity development. This proliferation was mainly observed in the hypothalamus (HT), a crucial brain structure for controlling body weight. Therefore, we sought to characterize the post-prandial HT inflammatory response to 1-3-6 hours exposure to a standard diet and HFD. HFD exposure increased gene expression of astrocyte and microglial marker (GFAP and Iba1) compare to standard treated mice and induced morphological modifications of microglial cells in HT. This remodeling was associated with higher expression of inflammatory genes and differential activation of hypothalamic neuropeptides involved in energy balance regulation. DREADD and PLX5622 technologies, used to modulate GFAP-positive or microglial cells activity respectively, showed that both glial cell types are involved in hypothalamic post-prandial inflammation, but in a different time frame and with a diet specificity Thus, an exacerbated post-prandial inflammation in brain might predispose individuals to obesity and needs to be characterized to address this worldwide crisis.
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- 2019
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18. Sortilin-derived peptides promote pancreatic beta-cell survival through CREB signaling pathway
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Sophie Béraud-Dufour, Guillaume Daziano, Nicolas Blondeau, Jean Mazella, Amar Abderrahmani, Patricia Lebrun, Catherine Heurteaux, Thierry Coppola, Carole Rovère, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), NanoBioInterfaces - IEMN (NBI - IEMN), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), ANR-13-SAMA-0002,VASPAC,Validation du concept spadine pour le traitement de la dépression(2013), ANR-13-RPIB-0002,MEDINCOD,Médication d'un Nouveau Concept pour la Dépression(2013), ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), and Université catholique de Lille (UCL)-Université catholique de Lille (UCL)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA)
- Subjects
0301 basic medicine ,Cell Survival ,CREB activation ,Beta-cell protection ,Endogeny ,Type 2 diabetes ,CREB ,Calcium in biology ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Insulin-Secreting Cells ,Calcium influx ,Insulin Secretion ,medicine ,Animals ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Cyclic AMP Response Element-Binding Protein ,Transcription factor ,Pharmacology ,biology ,Chemistry ,Sortilin-released propeptide ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,medicine.disease ,Rats ,Cell biology ,Adaptor Proteins, Vesicular Transport ,Neuropeptide ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,030220 oncology & carcinogenesis ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,biology.protein ,Phosphorylation ,Signal transduction ,Beta cell ,Peptides ,Signal Transduction - Abstract
International audience; Deterioration of insulin secretion and pancreatic beta-cell mass by inflammatory attacks is one of the main pathophysiological features of type 2 diabetes (T2D). Therefore, preserving beta-cell mass and stimulating insulin secretion only in response to glucose for avoiding the hypoglycemia risks, are the most state-of-the-art option for the treatment of T2D. In this study we tested two correlated hypothesis that 1/ the endogenous peptide released from sortilin, known as PE, that stimulates insulin secretion only in response to glucose, protects beta-cells against death induced by cytokines, and 2/ Spadin and Mini-Spadin, two synthetic peptides derived from PE, that mimic the effects of PE in insulin secretion, also provide beneficial effect on beta-cells survival. We show that PE and its derivatives by inducing a rise of intracellular calcium concentration by depolarizing the membrane protect beta-cells against death induced by Interleukin-1β. Using biochemical, confocal imaging and cell biology techniques, we reveal that the protective effects of PE and its derivatives rely on the activation of the CaM-Kinase pathway, and on the phosphorylation and activation of the transcription factor CREB. In addition, Mini-Spadin promotes beta-cell proliferation, suggesting its possible regenerative effect. This study highlights new possible roles of PE in pancreatic beta-cell survival and its derivatives as pharmacological tools against diabetes.
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- 2021
19. Bridging the Gap Between Diabetes and Stroke in Search of High Clinical Relevance Therapeutic Targets
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Sophie Béraud-Dufour, Nicolas Blondeau, Patricia Lebrun, Thierry Coppola, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), and Université de Nice Sophia-Antipolis (UNSA)
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0301 basic medicine ,Exacerbation ,Brain ischemia ,0302 clinical medicine ,Risk Factors ,Prevalence ,tolerance to brain ischemia ,Tissues and Organs (q-bio.TO) ,Stroke ,Metabolic Syndrome ,Clinical Trials as Topic ,3. Good health ,comorbidity ,Neuroprotective Agents ,Neurology ,Cardiovascular Diseases ,Molecular Medicine ,Neurons and Cognition (q-bio.NC) ,Brain Damage, Chronic ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Signal Transduction ,medicine.medical_specialty ,Hyperlipidemias ,Neuroprotection ,Diabetes Complications ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,glucolipotoxicity ,Diabetes mellitus ,medicine ,Diabetes Mellitus ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Humans ,Hypoglycemic Agents ,Clinical significance ,Obesity ,Risk factor ,Intensive care medicine ,Ischemic Stroke ,business.industry ,Quantitative Biology - Tissues and Organs ,medicine.disease ,Comorbidity ,Diet ,signaling pathways ,Disease Models, Animal ,030104 developmental biology ,Quantitative Biology - Neurons and Cognition ,FOS: Biological sciences ,Hyperglycemia ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Sedentary Behavior ,business ,030217 neurology & neurosurgery - Abstract
Diabetes affects more than 425 million people worldwide, a scale approaching pandemic proportion. Diabetes represents a major risk factor for stroke, and therefore is actively addressed for stroke prevention. However, how diabetes affects stroke severity has not yet been extensively considered, which is surprising given the evident but understudied common mechanistic features of both pathologies. The increase in number of diabetic people, in the incidence of stroke in presence of this specific risk factor, and the exacerbation of ischemic brain damage in diabetic conditions (at least in animal models) warrant the need to integrate this comorbidity in pre-clinical studies of brain ischemia to develop novel therapeutic approaches. Therefore, a better understanding of the commonalties involved in the course of both diseases would offer the promise of discovering novel neuroprotective pathways that would be more appropriated to clinical situations. In this article, we will review the relevant mechanisms that have been identified as common traits of both pathologies and that could be to our knowledge, potential targets for both pathologies., Comment: NeuroMolecular Medicine, Humana Press, 2019
- Published
- 2019
20. An acute coronary syndrome in Antarctica
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Jacques Levraut, Mathieu Carron, Fanny Hamard, Nicolas Blondeau, Université Nice Sophia Antipolis - Faculté de Médecine (UNS UFR Médecine), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Service de réanimation, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital St Roch, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
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Male ,Acute coronary syndrome ,medicine.medical_specialty ,Chest Pain ,cruise ship ,[SDV]Life Sciences [q-bio] ,Cruise ,Antarctic Regions ,Chest pain ,Electrocardiography ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Peninsula ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,medicine ,Acute chest pain ,Humans ,Myocardial infarction ,Acute Coronary Syndrome ,Naval Medicine ,Cold weather ,Weather ,Ships ,Aged ,geography ,geography.geographical_feature_category ,business.industry ,General Medicine ,medicine.disease ,Troponin ,myocardial infarction ,Emergency medicine ,Antarctica ,medicine.symptom ,business ,Bay ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Cruise tourism to Antarctica is constantly growing. Passengers and crewmembers may experience illnesses or injuries while traveling to remote areas with harsh weather conditions from where prompt evacuation is mostly unavailable. While a small explorer ship was at Wilhelmina bay (64°39' South and 62°08' West) in the Antarctic Peninsula, a 73-year-old male passenger presented with acute chest pain after two short excursions off the vessel in cold weather conditions. He was treated on board and remained clinically stable until the ship reached Ushuaia at the end of the cruise which was 5 days after the symptoms onset. (Int Marit Health 2019; 70, 3: 1-4)
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- 2019
21. Sortilin in Glucose Homeostasis: From Accessory Protein to Key Player?
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Sophie Béraud-Dufour, Patricia Lebrun, Nicolas Blondeau, Céline Hivelin, Thierry Coppola, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia-Antipolis (UNSA), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA)
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0301 basic medicine ,medicine.medical_treatment ,Mini Review ,receptor ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,Cell fate determination ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Glucose homeostasis ,Pharmacology (medical) ,Receptor ,ComputingMilieux_MISCELLANEOUS ,diabetes ,Effector ,Growth factor ,lcsh:RM1-950 ,Insulin receptor ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,chemistry ,030220 oncology & carcinogenesis ,physiology ,biology.protein ,pharmacology ,signaling ,Neuroscience ,Function (biology) ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Neurotensin - Abstract
International audience; The pharmacological properties and physiological roles of the type I receptor sortilin, also called neurotensin receptor-3, are various and complex. Sortilin is involved in important biological functions from neurotensin and pro-Nerve Growth Factor signaling in the central nervous system to regulation of glucose and lipid homeostasis in the periphery. The peripheral functions of sortilin being less extensively addressed, the focus of the current review is to discuss recent works describing sortilin-induced molecular mechanisms regulating blood glucose homeostasis and insulin signaling. Thus, an overview of several roles ascribed to sortilin in diabetes and other metabolic diseases are presented. Investigations on crucial cellular pathways involved in the protective effect of sortilin receptor on beta cells, including recent discoveries about regulation of cell fate, are also detailed. In addition, we provide a special focus on insulin secretion regulation involving complexes between sortilin and neurotensin receptors. The last section comments on the future research areas which should be developed to address the function of new effectors of the sortilin system in the endocrine apparatus.
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- 2019
22. The nutraceutical potential of omega-3 alpha-linolenic acid in reducing the consequences of stroke
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Nicolas Blondeau, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
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0301 basic medicine ,Neurogenesis ,[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Ischemia ,Bioinformatics ,Biochemistry ,Neuroprotection ,Brain Ischemia ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Nutraceutical ,Animals ,Humans ,Medicine ,Risk factor ,Stroke ,Brain preconditioning ,chemistry.chemical_classification ,Clinical Trials as Topic ,business.industry ,alpha-Linolenic acid ,Functional food ,alpha-Linolenic Acid ,General Medicine ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,medicine.disease ,3. Good health ,therapeutic ,Neuroprotective Agents ,030104 developmental biology ,chemistry ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Synaptogenesis ,business ,Essential nutrient ,pharmacokinetics ,metabolism ,030217 neurology & neurosurgery ,Polyunsaturated fatty acid - Abstract
International audience; Stroke is a worldwide major cause of mortality and morbidity. Preclinical studies have identified over 1000 molecules with brain-protective properties. More than 200 clinical trials have evaluated neuroprotective candidates for ischemic stroke yet, to date almost all failed, leading to a re-analysis of treatment strategies against stroke. An emerging view is to seek combinatory therapy, or discovering molecules able to stimulate multiple protective and regenerative mechanisms. A pertinent experimental approach to identify such candidates is the study of brain preconditioning, which refers to how the brain protects itself against ischemia and others stress-inducing stimuli. The recent discovery that nutrients like alpha-linolenic acid (ALA is an essential omega-3 polyunsaturated fatty acid required as part of our daily diet), may be an efficient brain preconditionner against stroke fosters the novel concept of brain preconditioning by nutraceuticals. This review stresses the underestimated role of nutrition in preventing and combating stroke. Although there is a consensus that increased consumption of salt, fatty foods and alcoholic beverages may promote pathologies like hypertension, obesity and alcoholism - all of which are well known risk factors of stroke - few risk factors are attributed to a deficiency in an essential nutrient in the diet. The ALA deficiency observed in the Western modern diets may itself constitute a risk factor. This review outlines how ALA supplementation by modification of the daily diet prevented mortality and cerebral damage in a rodent model of ischemic stroke. It also describes the pleiotropic ability of ALA to trigger responses that are multicellular, mechanistically diverse, resulting in neuronal protection, stimulation of neuroplasticity, and brain artery vasodilation. Overall, this review proposes a promising therapeutic opportunity by integrating a nutritional-based approach focusing on enriching the daily diet in ALA to prevent the devastating damage caused by stroke.
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- 2016
23. Ionic Homeostasis Maintenance in ALS: Focus on New Therapeutic Targets
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Natascia Guida, Giuseppe Pignataro, Salvatore Amoroso, Pasquale Cepparulo, Nicolas Blondeau, Paola Brancaccio, Lucio Annunziato, Lorella M.T. Canzoniero, Valeria Valsecchi, Antonio Vinciguerra, Rossana Sirabella, Serenella Anzilotti, Ornella Cuomo, Cristina Franco, Sirabella, Rossana, Valsecchi, Valeria, Anzilotti, Serenella, Cuomo, Ornella, Vinciguerra, Antonio, Cepparulo, Pasquale, Brancaccio, Paola, Guida, Natascia, Blondeau, Nicola, Canzoniero, Lorella M T, Franco, Cristina, Amoroso, Salvatore, Annunziato, Lucio, Pignataro, Giuseppe, Neuroscienze, Unità di Farmacologia, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Department of Economics, and Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO)
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0301 basic medicine ,ionic homeostasi ,[SDV]Life Sciences [q-bio] ,SOD1 ,channel ,Review ,Disease ,transporters ,channels ,lcsh:RC321-571 ,ionic homeostasis ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Amyotrophic lateral sclerosis ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,ComputingMilieux_MISCELLANEOUS ,business.industry ,General Neuroscience ,Neurodegeneration ,neurodegeneration ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,medicine.disease ,Spinal cord ,Pathophysiology ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Brainstem ,ALS ,business ,Neuroscience ,030217 neurology & neurosurgery ,Motor cortex - Abstract
Amyotrophic lateral sclerosis (ALS) is one of the most threatening neurodegenerative disease since it causes muscular paralysis for the loss of Motor Neurons in the spinal cord, brainstem and motor cortex. Up until now, no effective pharmacological treatment is available. Two forms of ALS have been described so far: 90% of the cases presents the sporadic form (sALS) whereas the remaining 10% of the cases displays the familiar form (fALS). Approximately 20% of fALS is associated with inherited mutations in the Cu, Zn-superoxide dismutase 1 (SOD1) gene. In the last decade, ionic homeostasis dysregulation has been proposed as the main trigger of the pathological cascade that brings to motor-neurons loss. In the light of these premises, the present review will analyze the involvement in ALS pathophysiology of the most well studied metal ions, i.e., calcium, sodium, iron, copper and zinc, with particular focus to the role of ionic channels and transporters able to contribute in the regulation of ionic homeostasis, in order to propose new putative molecular targets for future therapeutic strategies to ameliorate the progression of this devastating neurodegenerative disease.
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- 2018
- Full Text
- View/download PDF
24. Requirement for preclinical prioritization of neuroprotective strategies in stroke: Incorporation of preconditioning
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Joseph S., Tauskela, Nicolas, Blondeau, National Research Council of Canada, Human Health Therapeutics, Department of Translational Bioscience, 1200 Montreal Road, Ottawa, Ontario, Canada K1A 0R6, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
- Subjects
FOS: Biological sciences ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Quantitative Biology - Tissues and Organs ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,Tissues and Organs (q-bio.TO) - Abstract
International audience; Acute neuroprotection in numerous human clinical trials has been an abject failure. Major systemic-and procedural-based issues have subsequently been identified in both clinical trials and preclinical animal model experimentation. As well, issues related to the neuroprotective moiety itself have contributed to clinical trial failures, including late delivery, mono-targeting, low potency and poor tolerability. Conditioning (pre-or post-) strategies can potentially address these issues and are therefore gaining increasing attention as approaches to protect the brain from cerebral ischemia. In principle, conditioning can address concerns of timing (preconditioning could be pre-emptively applied in high-risk patients, and post-conditioning after patients experience an unannounced brain infarction) and signaling (multi-modal). However, acute neuroprotection and conditioning strategies face a common translational issue: a myriad of possibilities exist, but with no strategy to select optimal candidates. In this review, we argue that what is required is a neuroprotective framework to identify the "best" agent(s), at the earliest investigational stage possible. This may require switching mindsets from identifying how neuroprotection can be achieved to determining how neuroprotection can fail, for the vast majority of candidates. Understanding the basis for failure can in turn guide supplementary treatment, thereby forming an evidence-based rationale for selecting combinations of therapies. An appropriately designed in vitro (neuron culture, brain slices) approach, based on increasing the harshness of the ischemic-like insult, can be useful in identifying the "best" conditioner or acute neuroprotective therapy, as well as how the two modalities can be combined to overcome individual limitations. This would serve as a base from which to launch further investigation into therapies required to protect the neurovascular unit in in vivo animal models of cerebral ischemia. Based on these respective approaches, our laboratories suggest that there is merit in examining synaptic activity-and nutraceutical-based preconditioning / acute neuroprotection.
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- 2018
25. Cruise ship pathologies in remote regions
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Nicolas Emeyriat, Mathieu Carron, Nicolas Blondeau, Jacques Levraut, Université Nice Sophia Antipolis - Faculté de Médecine (UNS UFR Médecine), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Service de réanimation, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital St Roch, Institut de pharmacologie moléculaire et cellulaire (IPMC), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
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Adult ,Male ,medicine.medical_specialty ,Emergency Medical Services ,Adolescent ,030231 tropical medicine ,Cruise ,Antarctic Regions ,Communicable Diseases ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,medicine ,Allergic dermatitis ,Humans ,Prospective Studies ,Medical diagnosis ,Child ,Naval Medicine ,Stroke ,ComputingMilieux_MISCELLANEOUS ,Fisher's exact test ,Ships ,Aged ,Aged, 80 and over ,Travel ,business.industry ,Arctic Regions ,Incidence ,030208 emergency & critical care medicine ,General Medicine ,Middle Aged ,medicine.disease ,3. Good health ,The arctic ,Cross-Sectional Studies ,Cardiovascular Diseases ,Emergency medicine ,symbols ,International Classification of Primary Care ,Wounds and Injuries ,Observational study ,Female ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Background: Navigations on cruise ships are rising and tend to spread to remote areas like polar regions. Our aim was to assess the prevalence of pathologies encountered on a cruise ship navigating in remote areas including Polar Seas. Materials and methods: A prospective observational, descriptive and cross-sectional study was conducted aboard a cruise ship with an overall capacity of 200–264 passengers and 140 crewmembers, sailing in remote areas as the Arctic Ocean and the Antarctic Peninsula over a period of 205 days. The database was built on all first consultations for passengers and crewmembers done by the onboard physician. Each symptom and diagnosis was coded according to the “International Classification of Primary Care, 2 nd edition”. For statistical analysis, the quantitative data were expressed as mean ± standard deviation and qualitative data as percentages. The percentages were compared using a c 2 test corrected according to the Yates’ method or by a Fisher test when appropriate. Results: A total of 446 diagnoses were studied on the 910 consultations originally included (13.7% of the people on board). The median age for the passengers and the crewmembers was respectively 68 (age ranging from 12 to 90) years and 31 (18–62) years. Likewise, the sex ratio (male/female) was 0.98 and 3.23. Infectious diseases were predominant (prevalence of 43.7%). Among them, respiratory infections were the most common and gastroenteritis seemed to be more frequent in passengers (prevalence of 11.5% vs. 5%, p = 0.10). Cutaneous pathologies were more frequent in crewmembers (prevalence of 26.6% vs. 18.7%, p = 0.04) and allergic dermatitis was the second most frequent in this group of patients (prevalence of 7.2%). Cardiovascular diseases, more common in passengers (p = 0.05), represented 4% of all diagnoses. Two cases of phlebitis, one stroke and one subacute heart failure were diagnosed. Among traumatic injuries, cutaneous traumas were the commonest (prevalence of 76.5%). Musculoskeletal traumas were more common in passengers (p = 0.04). An acute gastrointestinal haemorrhage required a medical evacuation from the Antarctic Peninsula. Conclusions: The physician should be prepared to face emergency cases by developing personal expertise specific to maritime medicine in remote areas. Highlighting the particularity of cases handled in remote areas, our results should also pave the way of the development of medical protocols for ships lacking physician.
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- 2018
26. The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects
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Ophélia Le Thuc, Nicolas Blondeau, Carole Rovère, and Jean-Louis Nahon
- Subjects
Chemokine ,Central nervous system ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,History and Philosophy of Science ,Medicine ,Neuroinflammation ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,General Neuroscience ,medicine.disease ,Neuromodulation (medicine) ,medicine.anatomical_structure ,Immunology ,biology.protein ,medicine.symptom ,Alzheimer's disease ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Inflammation is an innate mechanism that defends organisms against harmful stimuli. Inflammation leads to the production and secretion of proinflammatory mediators that activate and recruit immune cells to damaged tissues, including the brain, to resolve the cause of inflammation. In the central nervous system, inflammation is referred to as neuroinflammation, which occurs in various pathological conditions of the brain. The primary role of neuroinflammation is to protect the brain. However, prolonged and/or inappropriate inflammation can be harmful for the brain, from individual cells to the whole tissue. This review focuses on a particular type of inflammatory mediator, chemokines, and describes their complex effects both under physiological and pathophysiological conditions of the brain. The clinical relevance of the multiple characters of chemokines is highlighted with respect to acute and chronic inflammation of the brain, including their actions in stroke and Alzheimer's disease, respectively.
- Published
- 2015
27. Central CCL2 signaling onto MCH neurons mediates metabolic and behavioral adaptation to inflammation
- Author
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Nadège Devaux, Serge Luquet, Katharina Stobbe, Raphael G. P. Denis, Carole Rovère, Miled Bourourou, Céline Cansell, Jean-Louis Nahon, Julie Cazareth, Ophélia Le Thuc, William Rostène, Nicolas Blondeau, Alice Guyon, Catherine Heurteaux, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Station de primatologie (SP), Centre National de la Recherche Scientifique (CNRS), and Blondeau, Nicolas
- Subjects
0301 basic medicine ,Lipopolysaccharides ,Chemokine ,Melanin-concentrating hormone ,[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,CCR2 signaling pathway ,[SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Biochemistry ,neuroinflammation ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Sickness behavior ,ComputingMilieux_MISCELLANEOUS ,Chemokine CCL2 ,Illness Behavior ,Neurons ,Hypothalamic Hormones ,biology ,[SDV] Life Sciences [q-bio] ,Cytokines ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,medicine.symptom ,Signal transduction ,medicine.drug ,Signal Transduction ,medicine.medical_specialty ,Receptors, CCR2 ,melanin‐concentrating hormone ,Hypothalamus ,Neuropeptide ,Inflammation ,03 medical and health sciences ,CCL2 chemokine ,Internal medicine ,Orexigenic ,Weight Loss ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Genetics ,medicine ,Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Molecular Biology ,Neuroinflammation ,Melanins ,Scientific Reports ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Pituitary Hormones ,030104 developmental biology ,Endocrinology ,chemistry ,biology.protein ,030217 neurology & neurosurgery - Abstract
International audience; Sickness behavior defines the endocrine, autonomic, behavioral, and metabolic responses associated with infection. While inflammatory responses were suggested to be instrumental in the loss of appetite and body weight, the molecular underpinning remains unknown. Here, we show that systemic or central lipopolysaccharide (LPS) injection results in specific hypothalamic changes characterized by a precocious increase in the chemokine ligand 2 (CCL2) followed by an increase in pro-inflammatory cytokines and a decrease in the orexigenic neuropeptide melanin-concentrating hormone (MCH). We therefore hypothesized that CCL2 could be the central relay for the loss in body weight induced by the inflammatory signal LPS. We find that central delivery of CCL2 promotes neuroinflammation and the decrease in MCH and body weight. MCH neurons express CCL2 receptor and respond to CCL2 by decreasing both electrical activity and MCH release. Pharmacological or genetic inhibition of CCL2 signaling opposes the response to LPS at both molecular and physiologic levels. We conclude that CCL2 signaling onto MCH neurons represents a core mechanism that relays peripheral inflammation to sickness behavior.
- Published
- 2016
28. Targeting eIF5A Hypusination Prevents Anoxic Cell Death through Mitochondrial Silencing and Improves Kidney Transplant Outcome
- Author
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Sandra Lacas-Gervais, Baharia Mograbi, Amine Belaid, Christophe Duranton, Marc Cougnon, Sébastien Giraud, Christian Frelin, Didier F. Pisani, Michel Tauc, Nicolas Melis, Nicolas Blondeau, Paul Vigne, Konstantina Fragaki, Stephan M. Huber, Thierry Hauet, Isabelle Rubera, Physiologie cellulaire et moléculaire des systèmes intégrés (PCMSI), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Service de Biochimie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Biologie Valrose (IBV), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), University of Konstanz, Centre Commun de Microscopie Appliquée (CCMA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Service de génétique médicale, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Neurobiologie Vasculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), and Transport Ionique Aspects Normaux et Pathologiques (TIANP), CNRS
- Subjects
0301 basic medicine ,MESH: Cell Death ,Male ,Swine ,[SDV]Life Sciences [q-bio] ,MESH: Cell Hypoxia ,Respiratory chain ,DHPS ,Mitochondrion ,MESH: Kidney Transplantation ,Mixed Function Oxygenases ,Mice ,0302 clinical medicine ,Peptide Initiation Factors ,Deoxyhypusine synthase ,MESH: Animals ,MESH: Peptide Initiation Factors ,MESH: Swine ,Cells, Cultured ,MESH: Treatment Outcome ,Kidney ,biology ,Cell Death ,Chemistry ,renal cell biology ,RNA-Binding Proteins ,General Medicine ,Deoxyhypusine Hydroxylase ,MESH: Mixed Function Oxygenases ,Cell Hypoxia ,Cell biology ,Mitochondria ,medicine.anatomical_structure ,Treatment Outcome ,Nephrology ,030220 oncology & carcinogenesis ,Female ,MESH: Cells, Cultured ,Programmed cell death ,MESH: Rats ,MESH: Mitochondria ,ischemia ,cell survival ,03 medical and health sciences ,MESH: Mice, Inbred C57BL ,medicine ,Gene silencing ,Animals ,MESH: Lysine ,Rats, Wistar ,MESH: Mice ,hypoxia ,Lysine ,transplant outcomes ,MESH: Rats, Wistar ,Kidney Transplantation ,MESH: Male ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,MESH: RNA-Binding Proteins ,Basic Research ,biology.protein ,MESH: Female - Abstract
International audience; The eukaryotic initiation factor 5A (eIF5A), which is highly conserved throughout evolution, has the unique characteristic of post-translational activation through hypusination. This modification is catalyzed by two enzymatic steps involving deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Notably, eIF5A may be involved in regulating the lifespan of Drosophila during long-term hypoxia. Therefore, we investigated the possibility of a link between eIF5A hypusination and cellular resistance to hypoxia/anoxia. Pharmacologic targeting of DHPS by N1-guanyl-1,7-diaminoheptane (GC7) or RNA interference-mediated inhibition of DHPS or DOHH induced tolerance to anoxia in immortalized mouse renal proximal cells. Furthermore, GC7 treatment of cells reversibly induced a metabolic shift toward glycolysis as well as mitochondrial remodeling and led to downregulated expression and activity of respiratory chain complexes, features characteristic of mitochondrial silencing. GC7 treatment also attenuated anoxia-induced generation of reactive oxygen species in these cells and in normoxic conditions, decreased the mitochondrial oxygen consumption rate of cultured cells and mice. In rats, intraperitoneal injection of GC7 substantially reduced renal levels of hypusinated eIF5A and protected against ischemia-reperfusion-induced renal injury. Finally, in the preclinical pig kidney transplant model, intravenous injection of GC7 before kidney removal significantly improved graft function recovery and late graft function and reduced interstitial fibrosis after transplant. This unconventional signaling pathway offers an innovative therapeutic target for treating hypoxic-ischemic human diseases and organ transplantation.
- Published
- 2016
29. Mutually Protective Actions of Kainic Acid Epileptic Preconditioning and Sublethal Global Ischemia on Hippocampal Neuronal Death: Involvement of Adenosine A 1 Receptors and K ATP Channels
- Author
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Catherine Heurteaux, Michel Lazdunski, Hélène Plamondon, Nicolas Blondeau, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,Potassium Channels ,Time Factors ,[SDV]Life Sciences [q-bio] ,Excitotoxicity ,Hippocampus ,Kainate receptor ,DNA laddering ,Pharmacology ,medicine.disease_cause ,030218 nuclear medicine & medical imaging ,chemistry.chemical_compound ,0302 clinical medicine ,Glyburide ,Ischemic Preconditioning ,ComputingMilieux_MISCELLANEOUS ,Neurons ,Kainic Acid ,Pyramidal Cells ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,Neuroprotective Agents ,Neurology ,Ischemic Attack, Transient ,Anesthesia ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Cardiology and Cardiovascular Medicine ,medicine.drug ,Kainic acid ,Ischemia ,DNA Fragmentation ,03 medical and health sciences ,Adenosine A1 receptor ,medicine ,In Situ Nick-End Labeling ,Animals ,Rats, Wistar ,Epilepsy ,business.industry ,Receptors, Purinergic P1 ,medicine.disease ,Adenosine ,Rats ,Disease Models, Animal ,chemistry ,Purinergic P1 Receptor Antagonists ,Xanthines ,Nerve Degeneration ,Phenylisopropyladenosine ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Preconditioning with sublethal ischemia attenuates the detrimental effects of subsequent prolonged ischemic insults. This research elucidates potential in vivo cross-tolerance between different neuronal death-generating treatments such as kainate administration, which induces seizures and global ischemia. This study also investigates the effects of a mild epileptic insult on neuronal death in rat hippocampus after a subsequent, lethal epileptic stress using kainic acid (KA) as a model of epilepsy. Three preconditioning groups were as follows: group 1 was injected with 5 mg/kg KA before a 6-minute global ischemia; group 2 received a 3-minute global ischemia before 7.5 mg/kg KA; and group 3 was injected with a 5-mg/kg dose of KA before a 7.5-mg/kg KA injection. The interval between treatments was 3 days. Neuronal degeneration, revealed by the silver impregnation method and analysis of cresyl violet staining, was markedly reduced in rats preconditioned with a sublethal ischemia or a 5-mg/kg KA treatment. Labeling with terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′triphosphate-biotin nick-end labeling and DNA laddering confirmed the component of DNA fragmentation in the death of ischemic and epileptic neurons and its reduction in all preconditioned animals. The current study supports the existence of bidirectional cross-tolerance between KA excitotoxicity and global ischemia and suggests the involvement of adenosine A1 receptors and sulfonylurea- and ATP-sensitive K+ channels in this protective phenomenon.
- Published
- 2016
30. Failure and rescue of preconditioning-induced neuroprotection in severe stroke-like insults
- Author
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Amy Aylsworth, Joseph S. Tauskela, Melissa Hewitt, Nicolas Blondeau, Eric Brunette, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Time Factors ,[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Excitotoxicity ,Severe stroke ,medicine.disease_cause ,Ouabain ,0302 clinical medicine ,Ischemia ,Medicine ,4-Aminopyridine ,Ischemic Preconditioning ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,Cerebral Cortex ,Neurons ,Glutamate receptor ,Cell Hypoxia ,Neuroprotection ,Stroke ,Neuroprotective Agents ,NMDA receptor ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,medicine.drug ,Glutamic Acid ,Preconditioning ,Bicuculline ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Animals ,Pharmacology ,Aspartic Acid ,business.industry ,medicine.disease ,Coculture Techniques ,Rats ,Glucose ,030104 developmental biology ,nervous system ,Dizocilpine Maleate ,business ,Tolerance ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Preconditioning is a well established neuroprotective modality. However, the mechanism and relative efficacy of neuroprotection between diverse preconditioners is poorly defined. Cultured neurons were preconditioned by 4-aminopyridine and bicuculline (4-AP/bic), rendering neurons tolerant to normally lethal (sufficient to kill most neurons) oxygen-glucose deprivation (OGD) or a chemical OGD-mimic, ouabain/TBOA, by suppression of extracellular glutamate (glutamateex) elevations. However, subjecting preconditioned neurons to longer-duration supra-lethal insults caused neurotoxic glutamateex elevations, thereby identifying a 'ceiling' to neuroprotection. Neuroprotective 'rescue' of neurons could be obtained by administration of an NMDA receptor antagonist, MK-801, just before glutamateex rose during these supra-lethal insults. Next, we evaluated if these concepts of glutamateex suppression during lethal OGD, and a neuroprotective ceiling requiring MK-801 rescue under supra-lethal OGD, extended to the preconditioning field. In screening a panel of 42 diverse putative preconditioners, neuroprotection against normally lethal OGD was observed in 12 cases, which correlated with glutamateex suppression, both of which could be reversed, either by the inclusion of a glutamate uptake inhibitor (TBOA, to increase glutamateex levels) during OGD or by exposure to supra-lethal OGD. Administrating MK-801 during the latter stages of supra-lethal OGD again rescued neurons, although to varying degrees dependent on the preconditioning agent. Thus, 'stress-testing' against the harshest ischemic-like insults yet tested identifies the most efficacious preconditioners, which dictates how early MK-801 needs to be administered during the insult in order to maintain neuroprotection. Preconditioning delays a neurotoxic rise in glutamateex levels, thereby 'buying time' for acute anti-excitotoxic pharmacologic rescue.
- Published
- 2016
31. Alpha-linolenic acid given as enteral or parenteral nutritional intervention against sensorimotor and cognitive deficits in a mouse model of ischemic stroke
- Author
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Miled Bourourou, Catherine Heurteaux, Nicolas Blondeau, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Parenteral Nutrition ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,medicine.medical_treatment ,Morris water navigation task ,Bioinformatics ,Neuroprotection ,Enteral administration ,Brain Ischemia ,Brain ischemia ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,Enteral Nutrition ,medicine ,Animals ,Cognitive Dysfunction ,Stroke ,ComputingMilieux_MISCELLANEOUS ,Nutrition ,Pharmacology ,business.industry ,alpha-Linolenic Acid ,Stroke outcome and recovery ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,medicine.disease ,3. Good health ,Surgery ,Motor coordination ,Disease modifiers ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Parenteral nutrition ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Polyunsaturated fatty acids ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Nutraceutical ,Stroke recovery ,business ,030217 neurology & neurosurgery ,Psychomotor Performance - Abstract
Stroke is a leading cause of disability and death worldwide. Numerous therapeutics applied acutely after stroke have failed to improve long-term clinical outcomes. An emerging direction is nutritional intervention with omega-3 polyunsaturated fatty acids acting as disease-modifying factors and targeting post-stroke disabilities. Our previous studies demonstrated that the omega-3 precursor, alpha-linolenic acid (ALA) administrated by injections or dietary supplementation reduces stroke damage by direct neuroprotection, and triggering brain artery vasodilatation and neuroplasticity. Successful translation of putative therapies will depend on demonstration of robust efficacy on common deficits resulting from stroke like loss of motor control and memory/learning. This study evaluated the value of ALA as adjunctive therapy for stroke recovery by comparing whether oral or intravenous supplementation of ALA best support recovery from ischemia. Motor and cognitive deficits were assessed using rotarod, pole and Morris water maze tests. ALA supplementation in diet was better than intravenous treatment in improving motor coordination, but this improvement was not due to a neuroprotective effect since infarct size was not reduced. Both types of ALA supplementation improved spatial learning and memory after stroke. This cognitive improvement correlated with higher survival of hippocampal neurons. These results support clinical investigation establishing therapeutic plans using ALA supplementation.
- Published
- 2016
32. α-linolenic omega-3 fatty acid for stroke protection: from brain preconditioning paradigm to nutrition
- Author
-
Nicolas Blondeau
- Subjects
Ischemia ,lcsh:TP670-699 ,Context (language use) ,Pharmacology ,Biochemistry ,Neuroprotection ,rapeseed oil ,prevention ,brain preconditioning and tolerance ,Medicine ,Omega 3 fatty acid ,Stroke ,omega-3 polyunsaturated fatty acids ,chemistry.chemical_classification ,business.industry ,Ischemic cascade ,medicine.disease ,stroke ,chemistry ,Cerebral blood flow ,nutraceutical ,lcsh:Oils, fats, and waxes ,business ,Food Science ,Polyunsaturated fatty acid - Abstract
Stroke is the third leading cause of death, due to its high incidence, the severity of the insult, and lack of treatment options. The only therapeutic is restoration of cerebral blood flow achieved by recombinant tissue plasminogen activator treatment, but only approximately 5% of patients receive it. In addition, therapeutics aimed at achieving neuroprotection by blocking the ischemic cascade, as identified in numerous preclinical studies, failed in clinical trials. This failure in translation from experimental models to clinical trials led to a re-evaluation of properties which would constitute the ‘‘best-in class’’ therapeutics to be used against stroke. Given that neuroprotection appears ineffective per se, an emerging direction is to identify therapies, probably combinatorial in nature, which protect the whole neurovascular unit and target timedependent neurotoxic mechanisms. Molecules that activate complex cellular signaling cascades that render the brain resistant to subsequent ischemia, known as preconditioners, offer a novel perspective in stroke protection. Preconditioning elicits complex endogenous neuroprotective responses that act by pleiotropic mechanisms to block death pathways, promote survival pathways and increase resistance. In addition to chemical preconditioners, natural/endogenous compounds such as adenosine, glutamate, lysophospholipids, and omega-3 polyunsaturated fatty acids have been demonstrated to be excellent preconditioners. Consequently, a major new concept in preconditioning to combat stroke is introduced, which is preconditioning achieved through supplementation of an essential item in diet or as a nutraceutical. Several epidemiologic studies suggested a beneficial effect of a seafood/omega-3-enriched diet in cerebral diseases, but the omega-3-induced protective mechanisms are still poorly identified. This review highlights how α-linolenic acid (ALA), the omega-3 polyunsaturated fatty acid precursor, protects the brain from in vivo and in vitro models of stroke, thus potentially fulfilling the goal of identifying the ‘‘best-in class’’ therapeutics against stroke. Also described is the surprising pleiotric nature of ALA in protecting neurons, vasodilating brain arteries and stimulating neuroplasticity. Importantly, feasibility of delivery has been demonstrated, since ALA supplementation can be achieved through modification of the daily diet, for which prevention of stroke-induced mortality and cerebral damage has been confirmed. Therefore evaluating ALA as an interesting preconditioner against stroke represents a novel and extremely relevant concept in the context of nutraceutical and functional food development.
- Published
- 2011
33. Peroxisome Proliferator-activated Receptor γ Induces Apoptosis and Inhibits Autophagy of Human Monocyte-derived Macrophages via Induction of Cathepsin L
- Author
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Mohamed-Naceur Slimane, Souliman Amrani, Thomas Simmet, Mustapha Rouis, Dler Faieeq Darweesh Mahmood, Tatiana Syrovets, El-Hadri Khadija, Nicolas Blondeau, Imene Jguirim-Souissi, and Vimala Diderot
- Subjects
chemistry.chemical_classification ,0303 health sciences ,Programmed cell death ,biology ,Autophagy ,Peroxisome proliferator-activated receptor ,Inflammation ,Cell Biology ,030204 cardiovascular system & hematology ,Biochemistry ,Cell biology ,Cathepsin L ,03 medical and health sciences ,0302 clinical medicine ,Bcl-2-associated X protein ,Downregulation and upregulation ,chemistry ,medicine ,biology.protein ,Glucose homeostasis ,medicine.symptom ,Molecular Biology ,030304 developmental biology - Abstract
Macrophages play a pivotal role in the pathophysiology of atherosclerosis. These cells express cathepsin L (CatL), a cysteine protease that has been implicated in atherogenesis and the associated arterial remodeling. In addition, macrophages highly express peroxisome proliferator-activated receptor (PPAR) γ, a transcription factor that regulates numerous genes important for lipid and lipoprotein metabolism, for glucose homeostasis, and inflammation. Hence, PPARγ might affect macrophage function in the context of chronic inflammation such as atherogenesis. In the present study, we examined the effect of PPARγ activation on the expression of CatL in human monocyte-derived macrophages (HMDM). Activation of PPARγ by the specific agonist GW929 concentration-dependently increased the levels of CatL mRNA and protein in HMDM. By promoter analysis, we identified a functional PPAR response element-like sequence that positively regulates CatL expression. In addition, we found that PPARγ-induced CatL promotes the degradation of Bcl2 without affecting Bax protein levels. Consistently, degradation of Bcl2 could be prevented by a specific CatL inhibitor, confirming the causative role of CatL. PPARγ-induced CatL was found to decrease autophagy through reduction of beclin 1 and LC3 protein levels. The reduction of these proteins involved in autophagic cell death was antagonized either by the CatL inhibitor or by CatL knockdown. In conclusion, our data show that PPARγ can specifically induce CatL, a proatherogenic protease, in HMDM. In turn, CatL inhibits autophagy and induces apoptosis. Thus, the proatherogenic effect of CatL could be neutralized by apoptosis, a beneficial phenomenon, at least in the early stages of atherosclerosis.
- Published
- 2011
34. Brain Poster Session: Neurogenesis
- Author
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Catherine Heurteaux, Jean-Christophe Plumier, Carine Nguemeni, David Debruyne, Marie Piens, Nicolas Blondeau, and Ann M. Marini
- Subjects
0303 health sciences ,business.industry ,alpha-Linolenic acid ,medicine.medical_treatment ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Neurology ,chemistry ,Neuroplasticity ,Medicine ,Anti depressant ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,Stroke recovery ,Neuroscience ,030217 neurology & neurosurgery ,030304 developmental biology - Published
- 2009
35. Brain Adaptation to Stressful Stimuli: A New Perspective on Potential Therapeutic Approaches Based on BDNF and NMDA Receptors
- Author
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Ann M. Marini, Margherita Popolo, Nicolas Blondeau, Hongna Pan, Robert H. Lipsky, Department of Neurology and Neurosciences Program, University of Health Sciences, Service EFSN, Hôpital Pasteur [Nice] (CHU), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), National Institute on Alcohol Abuse and Alcoholism, and Naional Institute of Health
- Subjects
[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Deoxyglucose ,MESH: Brain-Derived Neurotrophic Factor ,Receptors, N-Methyl-D-Aspartate ,Brain Ischemia ,MESH: Ischemic Preconditioning ,03 medical and health sciences ,0302 clinical medicine ,MESH: Spreading Cortical Depression ,Downregulation and upregulation ,Stress, Physiological ,Neurotrophic factors ,MESH: Propionic Acids ,Animals ,Humans ,MESH: Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Ischemic Preconditioning ,MESH: Stress, Physiological ,Receptor ,Transcription factor ,030304 developmental biology ,Pharmacology ,MESH: Receptors, N-Methyl-D-Aspartate ,0303 health sciences ,MESH: Humans ,Mechanism (biology) ,Brain-Derived Neurotrophic Factor ,General Neuroscience ,Cortical Spreading Depression ,MESH: Brain Ischemia ,MESH: Neuroprotective Agents ,Adaptive response ,Nitro Compounds ,MESH: Deoxyglucose ,Adaptation, Physiological ,MESH: Adaptation, Physiological ,MESH: Nitro Compounds ,Neuroprotective Agents ,Cortical spreading depression ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Propionates ,Signal transduction ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
International audience; A variety of sublethal or stressful stimuli induce a phenomenon in the brain known as tolerance, an adaptive response that protects the brain against the same stress, or against a different stress (cross-tolerance). Understanding the molecular mechanisms of brain preconditioning holds promise in developing innovative therapies to prevent and treat neurodegenerative disorders, particularly ischemic stroke. Many of the detailed steps involved in tolerance and cross-tolerance are unknown. It is also likely that different stressors differentially regulate sets of genes, transcription factors, and signal transduction pathways that depend upon the molecules that are released in response to the stressor, activation of particular receptors, and the surrounding milieu. The focus of this review is to highlight a few examples of stimuli that induce tolerance: 1) cortical spreading depression; 2) 3-nitropropionic acid; and 3) 2-deoxy-D-glucose. We will summarize by discussing one pathway where intracellular mediators may converge to upregulate intrinsic neuronal survival pathways to promote survival by resisting damage. This mechanism, activation of N-methyl-D-aspartate receptors and its integral relationship with brain-derived neurotrophic factor, may be a critical and general mechanism developed in brain to respond to stressful stimuli.
- Published
- 2008
36. Distribution of sphingosine kinase activity and mRNA in rodent brain
- Author
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Nicolas Blondeau, James K. Liao, Sarah Tyndall, James K. Pru, Christian Waeber, Kan Ding, Kamil Topalkara, Hyung-Hwan Kim, Margherita Popolo, Yushuan Lai, and Ling Zhang
- Subjects
0303 health sciences ,Cerebellum ,medicine.medical_specialty ,Sphingosine ,Sphingosine kinase ,Sphingosine Kinase 2 ,In situ hybridization ,Lipid signaling ,Biology ,Biochemistry ,Cell biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,SPHK2 ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Internal medicine ,medicine ,Sphingosine-1-phosphate ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Sphingosine-1-phosphate (S1P) is a lipid mediator that exerts multiple cellular functions through activation of a subfamily of G-protein-coupled receptors. Although there is evidence that S1P plays a role in the developing and adult CNS, little is known about the ability of brain parenchyma to synthesize this lipid. We have therefore analyzed the brain distribution of the enzymatic activity of the S1P synthesizing enzyme, sphingosine kinase (SPHK) [EC:2.7.1.91], as well as mRNA distribution for one of the two isoforms of this enzyme, sphingosine kinase 2. SPHK activity, measured by the conversion of [(3)H]sphingosine to [(3)H]S1P, is highest in cerebellum, followed by cortex and brainstem. Lowest activities were found in striatum and hippocampus. Sensitivity to 0.1% Triton-X suggests that this activity is accounted for by SPHK2. RT-PCR and in situ hybridization studies show that mRNA for this isoform has a distribution similar to that of SPHK activity. In vivo and in vitro ischemia increase SPHK activity and SPHK2 mRNA levels. These results indicate that SPHK2 is the predominant S1P-synthesizing isoform in normal brain parenchyma. Its heterogeneous distribution, in particular laminar distribution in cortex, suggests a neuronal localization and a possible role in cortical and cerebellar functions, in normal as well as ischemic brain.
- Published
- 2007
37. Altered acetylcholine, bradykinin and cutaneous pressure‐induced vasodilation in mice lacking the TREK1 potassium channel: the endothelial link
- Author
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Frédéric Brau, Michel Lazdunski, Ambroise Garry, Nicolas Blondeau, Bérengère Fromy, Daniel Henrion, Jean Louis Saumet, Catherine Heurteaux, Nicolas Guy, Pierre Gounon, Biologie Neurovasculaire Intégrée (BNVI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre commun de microscopie appliquée, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Loudig, Nadine, and Université Nice Sophia Antipolis (... - 2019) (UNS)
- Subjects
MESH: Mice, Mutant Strains ,MESH: Mesenteric Arteries ,Blood Pressure ,Vasodilation ,Biochemistry ,Mice ,chemistry.chemical_compound ,two-pore-domain K þ channel ,0302 clinical medicine ,MESH: Animals ,Endothelial dysfunction ,Mesenteric arteries ,0303 health sciences ,Chemistry ,MESH: Potassium Channels, Tandem Pore Domain ,MESH: Blood Pressure ,Potassium channel ,Mesenteric Arteries ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,medicine.anatomical_structure ,MESH: Endothelium, Vascular ,MESH: Pressure ,Acetylcholine ,medicine.drug ,skin ,medicine.medical_specialty ,Intracellular pH ,Scientific Report ,microcirculation ,Bradykinin ,Nitric Oxide ,Nitric oxide ,MESH: Vasodilation ,03 medical and health sciences ,Potassium Channels, Tandem Pore Domain ,MESH: Skin ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Internal medicine ,Pressure ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Genetics ,medicine ,Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: Mice ,Molecular Biology ,030304 developmental biology ,MESH: Capillaries ,MESH: Bradykinin ,MESH: Acetylcholine ,medicine.disease ,Mice, Mutant Strains ,Capillaries ,Endocrinology ,MESH: Gene Deletion ,MESH: Nitric Oxide ,Endothelium, Vascular ,Gene Deletion ,030217 neurology & neurosurgery - Abstract
The TWIK related K+ channel TREK1 is an important member of the class of two-pore-domain K+ channels. It is a background K+ channel and is regulated by hormones, neurotransmitters, intracellular pH and mechanical stretch. This work shows that TREK1 is present both in mesenteric resistance arteries and in skin microvessels. It is particularly well expressed in endothelial cells. Deletion of TREK1 in mice leads to an important alteration in vasodilation of mesenteric arteries induced by acetylcholine and bradykinin. Iontophoretic delivery of acetylcholine and bradykinin in the skin of TREK1+/+ and TREK1−/− mice also shows the important role of TREK1 in cutaneous endothelium-dependent vasodilation. The vasodilator response to local pressure application is also markedly decreased in TREK1−/− mice, mimicking the decreased response to pressure observed in diabetes. Deletion of TREK1 is associated with a marked alteration in the efficacy of the G-protein-coupled receptor-associated cascade producing NO that leads to major endothelial dysfunction.
- Published
- 2007
38. Alpha-Linolenic Acid: An Omega-3 Fatty Acid with Neuroprotective Properties—Ready for Use in the Stroke Clinic?
- Author
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Miled Bourourou, Mark W. Duncan, Philip B. Gorelick, Ann M. Marini, Robert H. Lipsky, Nicolas Blondeau, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Department of Neurology and Rehabilitation, and University of Illinois System
- Subjects
[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,lcsh:Medicine ,Review Article ,Bioinformatics ,Neuroprotection ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,Neurotrophic factors ,Neuroplasticity ,Fatty Acids, Omega-3 ,medicine ,Animals ,Humans ,Omega 3 fatty acid ,Stroke ,chemistry.chemical_classification ,Brain-derived neurotrophic factor ,General Immunology and Microbiology ,alpha-Linolenic acid ,business.industry ,Brain-Derived Neurotrophic Factor ,lcsh:R ,Brain ,alpha-Linolenic Acid ,General Medicine ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,medicine.disease ,3. Good health ,Neuroprotective Agents ,chemistry ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,business ,Polyunsaturated fatty acid - Abstract
International audience; Alpha-linolenic acid (ALA) is plant-based essential omega-3 polyunsaturated fatty acids that must be obtained through the diet. This could explain in part why the severe deficiency in omega-3 intake pointed by numerous epidemiologic studies may increase the brain's vulnerability representing an important risk factor in the development and/or deterioration of certain cardio- and neuropathologies. The roles of ALA in neurological disorders remain unclear, especially in stroke that is a leading cause of death. We and others have identified ALA as a potential nutraceutical to protect the brain from stroke, characterized by its pleiotropic effects in neuroprotection, vasodilation of brain arteries, and neuroplasticity. This review highlights how chronic administration of ALA protects against rodent models of hypoxic-ischemic injury and exerts an anti-depressant-like activity, effects that likely involve multiple mechanisms in brain, and may be applied in stroke prevention. One major effect may be through an increase in mature brain-derived neurotrophic factor (BDNF), a widely expressed protein in brain that plays critical roles in neuronal maintenance, and learning and memory. Understanding the precise roles of ALA in neurological disorders will provide the underpinnings for the development of new therapies for patients and families who could be devastated by these disorders.
- Published
- 2015
39. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype
- Author
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Catherine Heurteaux, Nicolas Guy, Malika El Yacoubi, Susanne Thümmler, Guillaume Lucas, Jean-Marie Vaugeois, Nicolas Blondeau, Marc Borsotto, Guy Debonnel, Xiao-Dong Peng, Gabriella Gobbi, Michel Lazdunski, Catherine Widmann, Florence Noble, Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Child Psychiatry, McGill University, Neuropsycho-pharmacologie expérimentale, Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Centre National de la Recherche Scientifique ( CNRS ), Pharmacochimie moléculaire et structurale, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Serotonin ,medicine.medical_specialty ,Genotype ,Drug Resistance ,Pharmacology ,Biology ,Neurotransmission ,Synaptic Transmission ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Potassium Channels, Tandem Pore Domain ,0302 clinical medicine ,Corticosterone ,Fluoxetine ,Internal medicine ,medicine ,Animals ,Neurotransmitter ,Depression (differential diagnoses) ,030304 developmental biology ,Mice, Knockout ,Analysis of Variance ,Depressive Disorder ,0303 health sciences ,Behavior, Animal ,Pyramidal Cells ,General Neuroscience ,Antidepressive Agents ,Potassium channel ,3. Good health ,Phenotype ,Endocrinology ,chemistry ,Antidepressant ,Gene Deletion ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Depression is a devastating illness with a lifetime prevalence of up to 20%. The neurotransmitter serotonin or 5-hydroxytryptamine (5-HT) is involved in the pathophysiology of depression and in the effects of antidepressant treatments. However, molecular alterations that underlie the pathology or treatment of depression are still poorly understood. The TREK-1 protein is a background K+ channel regulated by various neurotransmitters including 5-HT. In mice, the deletion of its gene (Kcnk2, also called TREK-1) led to animals with an increased efficacy of 5-HT neurotransmission and a resistance to depression in five different models and a substantially reduced elevation of corticosterone levels under stress. TREK-1–deficient (Kcnk2−/−) mice showed behavior similar to that of naive animals treated with classical antidepressants such as fluoxetine. Our results indicate that alterations in the functioning, regulation or both of the TREK-1 channel may alter mood, and that this particular K+ channel may be a potential target for new antidepressants.
- Published
- 2006
40. Les acides gras essentiels de la famille des oméga-3 et la santé de la mère et de l'enfant
- Author
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Stéphane M. Schneider and Nicolas Blondeau
- Subjects
2. Zero hunger ,Gynecology ,0303 health sciences ,medicine.medical_specialty ,Nutrition and Dietetics ,business.industry ,Endocrinology, Diabetes and Metabolism ,3. Good health ,Post-Partum Depression ,03 medical and health sciences ,0302 clinical medicine ,Internal Medicine ,medicine ,business ,Breast feeding ,030217 neurology & neurosurgery ,Unsaturated fatty acid ,030304 developmental biology - Abstract
Resume L'acide linoleique, precurseur des omega-6, et l'acide alphalinolenique, precurseur des omega-3, subissent differentes etapes metaboliques pour former, respectivement, l'acide arachidonique et les acides eicosapentaenoique et docohexaenoique. Il est recommande de respecter un rapport entre les apports en acide linoleique et en acide alpha-linolenique de 5 pour 1. Cependant, ce rapport n'est pas respecte dans l'alimentation de la population francaise, largement plus riche en omega-6 qu'en omega-3. Cette deficience, suspectee de favoriser la survenue de certains cancers et des maladies cardio- et neurovasculaires, est exacerbee chez la femme dans certaines situations physiologiques avec une forte augmentation des besoins comme la grossesse et l'allaitement. La carence en omega-3 pourrait etre liee chez la mere a un risque majore d'accouchement premature et de depression post-partum ; l'enrichissement du lait maternel en omega-3 favoriserait les fonctions visuelles et cognitives chez l'enfant. Une supplementation sous forme pharmacologique pourrait etre proposee durant cette periode.
- Published
- 2006
41. Alpha-Linolenic acid and riluzole treatment confer cerebral protection and improve survival after focal brain ischemia
- Author
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G. Jarretou, C. Laigle, Catherine Heurteaux, Michel Lazdunski, Nicolas Blondeau, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,Time Factors ,Cell Survival ,Blotting, Western ,Ischemia ,Pharmacology ,Neuroprotection ,Brain ischemia ,Palmitic acid ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Potassium Channels, Tandem Pore Domain ,0302 clinical medicine ,In Situ Nick-End Labeling ,medicine ,Animals ,030304 developmental biology ,0303 health sciences ,alpha-Linolenic acid ,business.industry ,2P-domain K ؉ channels ,General Neuroscience ,Brain ,alpha-Linolenic Acid ,Infarction, Middle Cerebral Artery ,medicine.disease ,Immunohistochemistry ,riluzole ,3. Good health ,Riluzole ,Mice, Inbred C57BL ,Neuroprotective Agents ,chemistry ,Anesthesia ,focal ischemia ,Saturated fatty acid ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Drug Therapy, Combination ,neuroprotection ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,business ,long-term survival ,Reperfusion injury ,030217 neurology & neurosurgery ,polyunsaturated fatty acids ,medicine.drug - Abstract
International audience; We investigated here the effects of alpha-linolenic acid and riluzole, both activators of the 2P-domain K ؉ channel family TREK/TRAAK, in a model of focal ischemia clinically relevant to stroke, not only assessing neuronal protection, but also long term survival. Moreover, all the drug treatments were initiated post-ischemia. Mice were subjected to transient middle cerebral artery occlusion (1 h) and reperfusion according to the intraluminal filament model. Drugs were injected into the jugular vein according to three protocols: (i) a single dose of 4 mg/kg riluzole or 500 nmol/kg alpha-linolenic acid at different reperfusion time; (ii) a three-day therapy (a single dose of 2 mg/kg riluzole and 250 nmol/kg alpha-linolenic acid given 1-2, 48 and 72 h after reperfusion); (iii) a three-week therapy (a single dose of 2 mg/kg riluzole and 250 nmol/kg alpha-linolenic acid given once a week during three weeks after reperfusion. A combined treatment with 2 mg/kg riluzole؉250 nmol/kg alpha-linolenic acid injected 2 h after reperfusion was also tested. A single dose of riluzole (4 mg/kg) or alpha-linolenic acid (500 nmol/kg) injected up to 3 h after reperfusion reduced drastically the stroke volume by 75% and 86%, respectively. Neurological deficits 24 h after ischemia were significantly improved by alpha-linolenic acid500 or riluzole4 with a neurological score of 1.8 as compared with 2.5 observed in vehicle-treated mice. Alpha-linolenic acid-and riluzole treatment were associated with a reduction in cytopathological features of cell injury, including DNA fragmentation and Bax expression in the cortex and the caudate putamen. With regard to the survival rate at 30 days, the best protections were obtained with the alpha-linolenic acid-injection in the threeweek therapy as well as with a single dose of the combined treatment (2 mg/kg riluzole؉250 nmol/kg alpha-linolenic acid). Palmitic acid, a saturated fatty acid that does not activate the 2P-domain K-channel TREK/TRAAK family, did not provide any neuroprotection. Taken together, these data suggest that the TREK/TRAAK K-channel family may be a promising target for neuroprotection, and that riluzole and alpha-linolenic acid could be of therapeutic value against focal ischemia/reperfusion injury to the brain.
- Published
- 2006
42. Le rôle majeur du canal potassique TREK-1 dans la protection neuronale induite par les oméga-3
- Author
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Catherine Heurteaux, Nicolas Blondeau, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
- Subjects
medicine.medical_specialty ,Neurology ,TREK-1 ,[SDV]Life Sciences [q-bio] ,Ischemia ,lcsh:TP670-699 ,Bioinformatics ,Biochemistry ,Neuroprotection ,cerebral ischemia ,Brain ischemia ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Essential fatty acid ,Medicine ,alpha linolenic acid (ALA) ,Unsaturated fatty acid ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,2P-domain K+ channels (K-2P) ,business.industry ,medicine.disease ,3. Good health ,chemistry ,epilepsy ,omega-3 ,lcsh:Oils, fats, and waxes ,business ,030217 neurology & neurosurgery ,Food Science ,Polyunsaturated fatty acid - Abstract
International audience; The nutritional interest of polyunsaturated fatty acids from omega-3, that are mainly present in vegetal and fish oils is now validated by the scientific community. Their beneficial effects have first been reported in coronary heart diseases. Many neurological and chronic diseases are often related to deficiencies in omega-3 and omega-6 and their derivatives. Polyunsaturated fatty acids from omega-3 family are essential to brain growth and neuronal preserving (foetuses, children, old people) as well as visual and cognitive functions. They are recently considered as factors of improvement in some mental diseases. Today, polyunsaturated fatty acids could play a key role in the prevention and/or or the treatment of cerebral diseases. With the development of in vitro and in vivo experimental models, it is now possible to demonstrate the omega-3-induced neuronal protection against major pathologies such as epileptic seizures and cerebral ischemia. The molecular mechanism of neuronal protection induced by omega-3 is now clarified. The omega-3 target would be a potassium channel, TREK-1, which belongs to the new family of 2-P domain potassium channels (K-2P). The discovery of the physiopathological role of these K-2P channels can represent an important therapeutical challenge not only in cerebrovascular diseases, but also in psychiatry.; Les acides gras polyinsaturés (AGPI), incorporés dans les phospholipides membranaires sont desconstituants structuraux fondamentaux du système nerveux central (SNC) dont la teneur conditionnele fonctionnement des cellules neuronales. Ils représentent environ 20 %de la matière sèchecérébrale et sont constitués des familles oméga-3 (n-3) et oméga-6 (n-6). Les acides grasprécurseurs de ces deux familles (acide alphalinolénique et acide linoléique) sont trouvés enquantités appréciables dans certaines huiles végétales (colza, noix et soja) et sont considéréscomme des acides gras essentiels. Ne pouvant pas être synthétisés de novo par l’homme et lesanimaux, leur apport ne peut se faire que par l’alimentation. L’acide alphalinolénique (ALA,18 :3n-3), précurseur des longues chaînes oméga-3, peut être transformé par l’homme en dérivésà longues chaînes (LC-n-3), dont les plus importants sont les acides eicosapentaénoïque (EPA,20:5n-3) et docosahexanoïque (DHA, 22:6n-3), qui peuvent aussi être apportés par la consommationde poissons gras. L’acide linoléique (LA, 18:2n-6), précurseur des oméga-6 est transformé parl’homme en acide arachidonique (AA, 20:4n-6), LC-n-6 que l’on trouve aussi dans les viandesanimales terrestres. Un déséquilibre dans le rapport LA/ALA dans l’apport alimentaire (optimal auxalentours de 5) est source de déséquilibres métaboliques et peut avoir de profondes répercussionssur divers processus physiologiques
- Published
- 2005
43. La tolérance cérébrale : un choix prometteur vers de nouvelles thérapies contre les maladies neurologiques
- Author
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Nicolas Blondeau, Catherine Heurteaux, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
- Subjects
Hyperthermia ,0303 health sciences ,business.industry ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Ischemia ,Retrospective cohort study ,General Medicine ,medicine.disease ,Bioinformatics ,Neuroprotection ,General Biochemistry, Genetics and Molecular Biology ,3. Good health ,Cross-tolerance ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Cortical spreading depression ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,medicine ,Ischemic preconditioning ,business ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Les accidents ischémiques et les crises épileptiques font partie des causes majeures de mort neuronale. Malgré les nombreuses recherches sur la neuroprotection et la découverte de nouvelles molécules capables de bloquer certains des événements délétères chez l’animal, peu de traitements sont disponibles pour lutter contre la mort neuronale induite par ces maladies. Le plus efficace reste le traitement thrombolytique en phase aiguë des accidents ischémiques cérébraux, qui ne peut toutefois être administré que chez une très faible population de patients. La prévention visant à réduire l’incidence des facteurs de risque reste donc la principale stratégie thérapeutique. La tolérance cérébrale est un phénomène endogène reposant sur l’induction préventive de la résistance neuronale. La compréhension de ses mécanismes permettrait d’identifier de nouvelles cibles thérapeutiques. Les inducteurs pharmacologiques de la tolérance cérébrale devraient conduire à la même neuroprotection et à la mise en oeuvre de nouvelles thérapeutiques., Ischemia and seizures are common diseases that result in neuronal death. To-date, there are no available treatments to block or reverse neuronal death pathways in patients who suffer from these diseases. All drugs that have been shown to be neuroprotective in animal models have failed in human trials. Therefore, the potential of preventative strategies for therapy is increasingly explored. Experimental studies have demonstrated that a brief cerebral ischemic insult, that is not harmful by itself, results in a temporary protective adaptation in the brain against a subsequent ischemic episode that would otherwise be lethal. This process, termed ischemic preconditioning, has been confirmed in different models of cerebral ischemia. A similar phenomenon observed after a mild epileptic insult conferred a transitory tolerance to a subsequent epileptic episode. This process is termed epileptic tolerance. Other stresses, like hyperthermia or spreading depression, also enhanced brain resistance to detrimental effects of ischemic or epileptic injury. Recently, a cross tolerance between ischemia and epilepsy has been reported. Also, some retrospective studies in humans suggest that endogenous ischemic preconditioning exists in the brain. Altogether these insights of brain tolerance point to the future discovery of potentially useful targets for acute neuroprotection as well as preventive therapy.
- Published
- 2004
44. Polyunsaturated fatty acids induce ischemic and epileptic tolerance
- Author
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Catherine Heurteaux, Nicolas Blondeau, M Lazdunski, Catherine Widmann, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
- Subjects
Male ,Kainic acid ,Programmed cell death ,Cell Survival ,Linolenic acid ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Ischemia ,Apoptosis ,Pharmacology ,Biology ,Hippocampus ,Neuroprotection ,Brain Ischemia ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,preconditioning ,medicine ,Animals ,Rats, Wistar ,forebrain ischemia ,030304 developmental biology ,Neurons ,chemistry.chemical_classification ,0303 health sciences ,General Neuroscience ,Neurodegeneration ,polyunsaturated fatty acid ,medicine.disease ,Immunohistochemistry ,Rats ,2-P domain K channels ,Hsp70 ,Oxidative Stress ,Neuroprotective Agents ,nervous system ,chemistry ,Biochemistry ,Fatty Acids, Unsaturated ,epilepsy ,030217 neurology & neurosurgery ,Polyunsaturated fatty acid - Abstract
International audience; The fndings reported in this work show that pretreatment with polyunsaturated fatty acids, particularly linolenic acid, present in vegetable oils, can provide a potent tolerance against neurodegeneration in two models of neuronal death-generating treatments such as kainic acid injection and global ischemia. Rats were injected i.v. with 500 nmol/kg of linolenic acid as long as 3 days prior to 6 min global ischemia or received an injection of linolenic acid as long as 3 days prior to a dose of 7.5 mg/kg kainic acid. Neuronal degeneration, assessed by analysis of neuronal density on Cresyl Violet-stained hippocampal sections, was signi¢cantly reduced in linolenic acid-treated rats (94^85% of cell survival in the ischemic model and 99^79% of cell survival in the epileptic model in respective CA1 and CA3 sub¢elds). The neuroprotection observed following the injection of linolenic acid 3 days prior to induction of a severe ischemic or epileptic challenge was associated with the induction of the neuroprotective HSP70 heat shock protein within the time window of protection. The injection of 500 nmol/kg of linolenic acid induced a maximal HSP70 expression of 387% at 72 h. In contrast, the overexpression of one well-known protein inducer of neuronal cell death, Bax, which is induced by both ischemic and kainic acid-induced epileptic insults, was prevented by linolenic acid in the 3-day window of protection. These results strengthen the idea of an interesting potential therapeutical value of polyunsaturated fatty acids in neuronal protection.
- Published
- 2002
45. Oxygen glucose deprivation-induced astrocyte dysfunction provokes neuronal death through oxidative stress
- Author
-
Alain Buisson, Lydia Kerkerian-Le Goff, André Nieoullon, Laurence Had-Aissouni, Joseph S. Tauskela, Elsa Gouix, Nicolas Blondeau, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
- Subjects
Pyridines ,Ischemia ,Carboxylic Acids ,Apoptosis ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,medicine.disease_cause ,Neuroprotection ,Antioxidants ,Astrocyte differentiation ,chemistry.chemical_compound ,Mice ,Glutamate transporters, Ischemia ,medicine ,Benzoquinones ,Animals ,Lipoxygenase Inhibitors ,Pharmacology ,Neurons ,Inflammation ,Caspase 3 ,Neurotoxicity ,ROS ,Glutathione ,medicine.disease ,Coculture Techniques ,Astrogliosis ,Cell biology ,Acetylcysteine ,Oxygen ,Oxidative Stress ,medicine.anatomical_structure ,Glucose ,chemistry ,nervous system ,Astrocytes ,Female ,Neuroscience ,Excitatory Amino Acid Antagonists ,Oxidative stress ,Astrocyte - Abstract
International audience; Understanding the role of astrocytes in stroke is assuming increasing prominence, not only as an important component on its own within the neurovascular unit, but also because astrocytes can influence neuronal outcome. Ischemia may induce astrogliosis and other phenotypic changes, but these remain poorly understood, in part due to limitations in reproducing these changes in vitro. Dibutyryl cyclic AMP-differentiated cultured astrocytes are more representative of the in vivo astroglial cell phenotype, and were much more susceptible than undifferentiated astrocytes to an ischemic-like stress, oxygen-glucose deprivation (OGD). OGD altered the expression/distribution and activity of glial glutamate transporters, impaired cellular glutamate uptake and decreased intracellular levels of glutathione preferentially in differentiated astrocytes. Resistance to OGD was conferred by inhibiting caspase-3 with DEVD-CHO and oxidative stress by the antioxidant N-acetylcysteine (NAC). The resistance of undifferentiated astrocytes to OGD may result from a transient but selective morphological transformation into Alzheimer type II astrocytes, an intermediary stage prior to transforming into reactive astrocytes. Co-culture of neurons with OGD-exposed astrocytes resulted in neurotoxicity, but at surprisingly lower levels with dying differentiated astrocytes. The antioxidant NAC or the 5-LOX inhibitor AA861 added upon co-culture delayed (day 1) but did not prevent neurotoxicity (day 3). Astrocytes undergoing apoptosis as a result of ischemia may represent a transient neuroprotective mechanism via ischemia-induced release of glutathione, but oxidative stress was responsible for neuronal demise when ischemia compromised astrocyte supportive functions.
- Published
- 2014
46. Polyunsaturated fatty acids are potent neuroprotectors
- Author
-
Georges Romey, Nicolas Blondeau, Inger Lauritzen, Michel Lazdunski, Catherine Widmann, Catherine Heurteaux, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
- Subjects
Kainic acid ,Potassium Channels ,Time Factors ,Linolenic acid ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Palmitic Acid ,Pharmacology ,Biology ,Hippocampus ,Neuroprotection ,General Biochemistry, Genetics and Molecular Biology ,Brain Ischemia ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Glutamatergic ,0302 clinical medicine ,Seizures ,In Situ Nick-End Labeling ,Animals ,Magnesium ,CYP2C8 ,Molecular Biology ,Cells, Cultured ,030304 developmental biology ,Neurons ,chemistry.chemical_classification ,Mice, Inbred BALB C ,0303 health sciences ,Kainic Acid ,Cell Death ,General Immunology and Microbiology ,General Neuroscience ,alpha-Linolenic Acid ,Articles ,Synapsins ,chemistry ,Biochemistry ,Docosahexaenoic acid ,Fatty Acids, Unsaturated ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Calcium ,Arachidonic acid ,030217 neurology & neurosurgery ,Polyunsaturated fatty acid - Abstract
International audience; Results reported in this work suggest a potential therapeutic value of polyunsaturated fatty acids for cerebral pathologies as previously proposed by others for cardiac diseases. We show that the polyunsatur-ated fatty acid linolenic acid prevents neuronal death in an animal model of transient global ischemia even when administered after the insult. Linolenic acid also protects animals treated with kainate against seizures and hippocampal lesions. The same effects have been observed in an in vitro model of seizure-like activity using glutamatergic neurons and they have been shown to be associated with blockade of glutamatergic transmission by low concentrations of distinct poly-unsaturated fatty acids. Our data suggest that the opening of background K + channels, like TREK-1 and TRAAK, which are activated by arachidonic acid and other polyunsaturated fatty acids such as docosahexa-enoic acid and linolenic acid, is a signi®cant factor in this neuroprotective effect. These channels are abundant in the brain where they are located both pre-and post-synaptically, and are insensitive to saturated fatty acids, which offer no neuroprotection.
- Published
- 2000
47. Alpha-linolenic acid: A promising nutraceutical for the prevention of stroke
- Author
-
Miled Bourourou, Elsa Gouix, Catherine Heurteaux, Nicolas Blondeau, Carine Nguemeni, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
medicine.medical_specialty ,030309 nutrition & dietetics ,[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Context (language use) ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Nutraceutical ,Medicine ,Pharmacology (medical) ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Risk factor ,Intensive care medicine ,Stroke ,ComputingMilieux_MISCELLANEOUS ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,business.industry ,alpha-Linolenic acid ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,medicine.disease ,Obesity ,3. Good health ,Surgery ,chemistry ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,business ,Essential nutrient ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Food Science ,Polyunsaturated fatty acid - Abstract
International audience; Stroke is a worldwide main cause of mortality and morbidity. Most of the preventive and neuroprotective treatments identified in preclinical studies failed in clinical trials. Although there is a consensus that nutrition is important for health, its role is underestimated in stroke. Indeed an increase consumption of salt and fatty foods may promote hypertension and obesity, which are well known risk factors of stroke. In contrast it is more difficult to identify a risk factor arising from a deficiency in an essential nutrient in the diet. Western modern diets are deficient in omega-3 polyunsaturated fatty acids, which are essential for brain health. Such deficiency may constitute by itself a risk factor for stroke. Furthermore, an imbalance in the consumption of omega-6 and omega-3 progressively took place in the past 40 years leading to omega-6/omega-3 ratios that are far above the WHO healthy recommendations. A consequence of this imbalanced ratio has been the fostering of elevations in and increased prevalence of inflammatory cardiovascular diseases and obesity. In this context, this review outlines a promising therapeutic opportunity by integrating a nutritional-based approach focusing on omega-3 alpha-linolenic acid as nutraceutical to prevent the devastating damage caused by brain ischemia.
- Published
- 2013
48. A New Future in Brain Preconditioning Based on Nutraceuticals: A Focus on α-Linolenic Omega-3 Fatty Acid for Stroke Protection
- Author
-
Nicolas Blondeau and Joseph S. Tauskela
- Subjects
Clinical trial ,Cell type ,Nutraceutical ,Cerebral blood flow ,business.industry ,Medicine ,Recombinant tissue plasminogen activator ,business ,medicine.disease ,Omega 3 fatty acid ,Bioinformatics ,Stroke ,Neuroprotection - Abstract
Stroke is a major cause of disability and death due to a high incidence rate, the severe and heterogeneous nature of the insult, poor recovery, and a paucity of treatments. The only currently clinically approved treatment is recombinant tissue plasminogen activator to restore cerebral blood flow, but eligibility requirements restrict this treatment to approximately 5 % of patients. Unfortunately, therapeutics designed to provide direct neuroprotection, by blocking the neurotoxic ischemic signaling cascade, as identified in numerous preclinical studies, failed in clinical trials. This failure in translation from experimental models to clinical trials suggests that defining criteria required for neuroprotection may have been too narrow in focus. Given the ineffectiveness of monotherapeutic strategies which target one cell type (neurons) and usually one signaling target, neuroprotection may only be achieved via therapeutics which are combinatorial in nature, targeting multiple cell types – the neurovascular unit – as well as multiple time-dependent neurotoxic mechanisms. Such a comprehensive approach sets more stringent standards but should ultimately yield the “best-in-class” therapeutic required to provide clinically relevant neuroprotection.
- Published
- 2012
49. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases
- Author
-
Gregory Conductier, Nicolas Blondeau, Alice Guyon, Carole Rovère, Jean-Louis Nahon, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)
- Subjects
CCR2 ,Chemokine ,MESH: Chemotaxis, Leukocyte ,0302 clinical medicine ,Neuroinflammation ,MESH: Receptors, CCR2 ,Immunology and Allergy ,MESH: Animals ,Chemokine CCL2 ,0303 health sciences ,biology ,Brain ,Alzheimer's disease ,3. Good health ,Stroke ,Chemotaxis, Leukocyte ,Neurology ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,medicine.symptom ,Chemokines ,CCL2 ,Monocyte Chemoattractant Proteins ,Multiple Sclerosis ,Receptors, CCR2 ,Immunology ,Inflammation ,MESH: Strok ,Lesion ,03 medical and health sciences ,MESH: Brain ,Immune system ,Alzheimer Disease ,medicine ,Animals ,Humans ,MESH: Chemokine CCL2 ,030304 developmental biology ,MESH: Humans ,business.industry ,Multiple sclerosis ,MESH: Multiple Sclerosis ,medicine.disease ,biology.protein ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,MESH: Alzheimer Disease - Abstract
International audience; Inflammatory response represents one of the first immune processes following injury. It is characterized by the production of various molecules that initiate the recruitment of immune cells to the lesion sites, including in the brain. Accordingly, in acute brain trauma, such as stroke, as well as during chronic affections like multiple sclerosis or Alzheimer's disease, inflammation occurs in order to "clean up" the lesion and to limit its area. Nevertheless, prolonged and sustained inflammation may have cytotoxic effects, aggravating the incidence and the severity of the disease. Among molecules produced during inflammation associated to neuronal death, monocyte chemoattractant proteins (MCPs) seem to be particularly important. This review will focus on the current knowledge about one of the MCPs, CCL2, and its cognate receptor, CCR2, both expressed in physiological conditions and during neurodegenerative diseases.
- Published
- 2010
50. Association of phenylbutazone usage with horses bought for slaughter: a public health risk
- Author
-
Nicholas H. Dodman, Ann M. Marini, Nicolas Blondeau, Cummings School of Veterinary Medicine, Tufts University [Medford], Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Department of Neurology and Neurosciences Program, and University of Health Sciences
- Subjects
Veterinary medicine ,Horse meat ,Toxicology ,0403 veterinary science ,0302 clinical medicine ,Medicine ,030212 general & internal medicine ,Racehorse ,biology ,Anti-Inflammatory Agents, Non-Steroidal ,04 agricultural and veterinary sciences ,General Medicine ,3. Good health ,Phenylbutazone ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Risk assessment ,Aplastic anemia ,Abattoirs ,medicine.drug ,Agranulocytosis ,medicine.medical_specialty ,food.ingredient ,Meat ,040301 veterinary sciences ,Food Contamination ,Race track ,Risk Assessment ,Food safety ,03 medical and health sciences ,food ,biology.animal ,Environmental health ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Horses ,Adverse effect ,United States Department of Agriculture ,business.industry ,United States Food and Drug Administration ,Public health ,Thoroughbred ,Drug Residues ,United States ,[SDV.ETH]Life Sciences [q-bio]/Ethics ,Residue ,Consumer Product Safety ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Equidae ,business ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition ,Food Science - Abstract
International audience; Sixty-seven million pounds of horsemeat derived from American horses were sent abroad for human consumption last year. Horses are not raised as food animals in the United States, and mechanisms to ensure the removal of horses treated with banned substances from the food chain are inadequate at best. Phenylbutazone (PBZ) is the most commonly used non-steroidal anti-inflammatory drug (NSAID) in equine practice. Thoroughbred (TB) race horses like other horse breeds are slaughtered for human consumption. Phenylbutazone is banned for use in any animal intended for human consumption because it causes serious and lethal idiosyncratic adverse effects in humans. The number of horses that have received phenylbutazone prior to being sent to slaughter for human consumption is unknown but its presence in some is highly likely. We identified eighteen TB race horses that were given PBZ on race day and sent for intended slaughter by matching their registered name to their race track drug record over a five year period. Sixteen rescued TB race horses were given PBZ on race day. Thus, PBZ residues may be present in some horsemeat derived from American horses. The permissive allowance of such horsemeat used for human consumption poses a serious public health risk.
- Published
- 2010
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