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16 results on '"MESH: Pituitary Adenylate Cyclase-Activating Polypeptide"'

1. Intranasal Administration of PACAP Is an Efficient Delivery Route to Reduce Infarct Volume and Promote Functional Recovery After Transient and Permanent Middle Cerebral Artery Occlusion

Author

Asma Cherait, Julie Maucotel, Benjamin Lefranc, Jérôme Leprince, David Vaudry, Lebon, Alexis, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Algiers 3 : Université d' Alger 3, Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), and Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Nasal cavity, functional recovery, Endocrinology, Diabetes and Metabolism, MESH: Neurotransmitter Agents, Pharmacology, infarct volume, lcsh:Diseases of the endocrine glands. Clinical endocrinology, cerebral ischemia, Mice, Endocrinology, 0302 clinical medicine, [CHIM] Chemical Sciences, MESH: Animals, MESH: Administration, Intranasal, Middle cerebral artery occlusion, Original Research, Neurotransmitter Agents, MESH: Infarction, Middle Cerebral Artery, Infarction, Middle Cerebral Artery, MESH: Neuroprotective Agents, MESH: Recovery of Function, pituitary adenylate cyclase-activating polypeptide, Neuroprotective Agents, medicine.anatomical_structure, Infarct volume, Brain Infarction, Central nervous system, Ischemia, Neuroprotection, intranasal administration, 03 medical and health sciences, MESH: Brain Infarction, MESH: Mice, Inbred C57BL, medicine, [CHIM]Chemical Sciences, Animals, MESH: Mice, Administration, Intranasal, lcsh:RC648-665, business.industry, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, Recovery of Function, medicine.disease, Functional recovery, MESH: Male, Mice, Inbred C57BL, 030104 developmental biology, Nasal administration, business, 030217 neurology & neurosurgery
Abstract

International audience; Intranasal (IN) administration appears to be a suitable route for clinical use as it allows direct delivery of bioactive molecules to the central nervous system, reducing systemic exposure and sides effects. Nevertheless, only some molecules can be transported to the brain from the nasal cavity. This led us to compare the efficiency of an IN, intravenous (IV), and intraperitoneal (IP) administration of pituitary adenylate cyclase-activating polypeptide (PACAP) after transient or permanent middle cerebral artery occlusion (MCAO) in C57BL/6 mice. The results show that the neuroprotective effect of PACAP is much more efficient after IN administration than IV injection while IP injection had no effect. IN administration of PACAP reduced the infarct volume when injected within 6 h after the reperfusion and improved functional recovery up to at least 1 week after the ischemia.

Published
2021
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2. Pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide promote the genesis of calcium currents in differentiating mouse embryonic stem cells

Author

Pierre Gressens, M. Chafai, William Rostène, Hubert Vaudry, M. Basille, Bruno J. Gonzalez, Estelle Louiset, Ludovic Galas, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie cellulaire des neurorécepteurs et physiopathologie neuroendocrinienne, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Normandie Université (NU), and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Cell Differentiation, MESH: Neural Stem Cells, Neurogenesis, Cellular differentiation, Vasoactive intestinal peptide, Biology, Real-Time Polymerase Chain Reaction, Mice, MESH: Gene Expression Profiling, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Gene Expression Regulation, Developmental, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, MESH: Animals, L-type calcium channel, MESH: Embryonic Stem Cells, MESH: Mice, Embryonic Stem Cells, 030304 developmental biology, 0303 health sciences, Voltage-dependent calcium channel, Reverse Transcriptase Polymerase Chain Reaction, MESH: Real-Time Polymerase Chain Reaction, Gene Expression Profiling, General Neuroscience, Calcium channel, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Vasoactive Intestinal Peptide, T-type calcium channel, Gene Expression Regulation, Developmental, Cell Differentiation, MESH: Immunohistochemistry, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Immunohistochemistry, Embryonic stem cell, Molecular biology, Neural stem cell, MESH: Neurogenesis, 3. Good health, MESH: Calcium Channels, Pituitary Adenylate Cyclase-Activating Polypeptide, Calcium Channels, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery, Vasoactive Intestinal Peptide
Abstract

International audience; Identification of novel molecules that can induce neuronal differentiation of embryonic stem (ES) cells is essential for deciphering the molecular mechanisms of early development and for exploring cell therapy approaches. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are known to be implicated early during ontogenesis in cell proliferation and neuronal differentiation. The aim of the present study was to determine the effects of VIP and PACAP on functional differentiation of ES cells. Quantitative-reverse transcription-polymerase chain reaction analysis showed an inversion of the expression pattern of PAC1 and VPAC1 receptors with time. ES cells expressed genes encoding extracellular signal-regulated kinase 1 and 2 and c-jun amino terminal kinase1. ES cells also expressed T-type α1I and α1G, L-type α1C and α1D, and N-type α1B calcium channel subunit mRNAs. Both peptides modified the shape of undifferentiated ES cells into bipolar cells expressing the neuronal marker neuron-specific enolase (NSE). Immunostaining indicated that PACAP intensified T-type α1I subunit immunoreactivity, whereas VIP increased L-types α1C and α1D, as well as N-type α1B subunit. Electrophysiological recording showed that VIP and PACAP enhanced transient calcium current. Moreover, VIP generated sustained calcium current. These findings demonstrate that PACAP and VIP induce morphological and functional differentiation of ES cells into a neuronal phenotype. Both peptides promote functional maturation of calcium channel subunits, suggesting that they can facilitate the genesis of cellular excitability.

Published
2011
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3. PACAP and a novel stable analog protect rat brain from ischemia: Insight into the mechanisms of action

Author

Omar Touzani, Alain Fournier, Steve Bourgault, David Vaudry, Hubert Vaudry, Agnieszka Dejda, Tommy Seaborn, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), International Associated laboratory Samuel de Champlain, Institut National de la Recherche Scientifique [Québec] (INRS)-Université de Rouen Normandie (UNIROUEN), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by INSERM, the European Institute for Peptide Research (IFRMP23), the Interreg 4A FEDER project TC2N, an ANR Jeune Chercheuse-Jeune Chercheur, the LARC Neurosciences network, and the Région Haute-Normandie, CHU Rouen, Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), and Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Inflammation, Physiology, Gene Expression, Apoptosis, Pharmacology, Biochemistry, MESH: Dose-Response Relationship, Drug, Brain ischemia, 0302 clinical medicine, Endocrinology, Drug Stability, Ischemia, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Caspase 3, MESH: Animals, bcl-2-Associated X Protein, 0303 health sciences, biology, Caspase 3, Reverse Transcriptase Polymerase Chain Reaction, Brain, MESH: Infarction, Middle Cerebral Artery, Nitric oxide synthase 2, Infarction, Middle Cerebral Artery, MESH: Neuroprotective Agents, Macrophage Inflammatory Proteins, 3. Good health, Stroke, Pituitary adenylate cyclase-activating peptide, Neuroprotective Agents, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Pituitary Adenylate Cyclase-Activating Polypeptide, medicine.symptom, medicine.medical_specialty, Programmed cell death, MESH: Gene Expression, MESH: Rats, MESH: Macrophage Inflammatory Proteins, Neuroprotection, MESH: Stroke, MESH: Brain, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Drug Stability, Internal medicine, medicine, Animals, MESH: bcl-2-Associated X Protein, RNA, Messenger, Rats, Wistar, MESH: RNA, Messenger, 030304 developmental biology, Inflammation, Dose-Response Relationship, Drug, Interleukin-6, Tumor Necrosis Factor-alpha, MESH: Apoptosis, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Rats, Wistar, medicine.disease, MESH: Interleukin-6, MESH: Male, Rats, Disease Models, Animal, Mechanism of action, MESH: Tumor Necrosis Factor-alpha, biology.protein, MESH: Ischemia, MESH: Disease Models, Animal, 030217 neurology & neurosurgery
Abstract

International audience; Pituitary adenylate cyclase-activating polypeptide (PACAP) shows potent protective effects in numerous models of neurological insults. However, the use of PACAP as a clinically efficient drug is limited by its poor metabolic stability. By combining identification of enzymatic cleavage sites with targeted chemical modifications, a metabolically stable and potent PACAP38 analog was recently developed. The neuroprotective activity of this novel compound was for the first time evaluated and compared to the native peptide using a rat model of middle cerebral artery occlusion (MCAO). Our results show that as low as picomolar doses of PACAP38 and its analog strongly reduce infarct volume and improve neurological impairment induced by stroke. In particular, these peptides inhibit the expression of Bcl-2-associated death promoter, caspase 3, macrophage inflammatory protein-1α, inducible nitric oxide synthase 2, tumor necrosis factor-α mRNAs, and increase extracellular signal-regulated kinase 2, B-cell CLL/lymphoma 2 and interleukin 6 mRNA levels. These results indicate that the neuroprotective effect of PACAP after MCAO is not only due to its ability to inhibit apoptosis but also to modulate the inflammatory response. The present study highlights the potential therapeutic efficacy of very low concentrations of PACAP or its metabolically stable derivative for the treatment of stroke.

Published
2011
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4. Pituitary adenylate cyclase-activating polypeptide inhibits caspase-3 activity but does not protect cerebellar granule neurons against β-amyloid (25–35)-induced apoptosis

Author

Alain Fournier, Hubert Vaudry, Magali Basille, Anthony Falluel-Morel, Bruno J. Gonzalez, David Vaudry, Cécile Cottet-Rousselle, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), and This work was supported by grants from INSERM (U413), an INSERM-FRSQ exchange program (to AF and HV) and the Conseil Regional de Haute-Normandie. A.F.M. was a recipient of a fellowship from the Conseil Régional de Haute-Normandie (LARC-Neuroscience network)

Subjects
β-amyloid peptide, Cerebellum, Physiology, Clinical Biochemistry, MESH: Neurons, Apoptosis, MESH: Neurotransmitter Agents, PACAP, MESH: Neuropeptides, Biochemistry, 0302 clinical medicine, Endocrinology, MESH: Caspase 3, Insulin, MESH: Animals, MESH: Peptide Fragments, Cells, Cultured, Caspase, Neurons, Neurotransmitter Agents, 0303 health sciences, biology, Caspase 3, Caspase Inhibitors, MESH: Amyloid beta-Peptides, Mitochondria, Cell biology, Pituitary adenylate cyclase-activating peptide, medicine.anatomical_structure, MESH: Cell Survival, Caspases, Enzyme Induction, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Cells, Cultured, medicine.medical_specialty, MESH: Enzyme Induction, MESH: Rats, MESH: Caspase Inhibitors, Neurite, Cell Survival, MESH: Mitochondria, MESH: Insulin, Cysteine Proteinase Inhibitors, Neuroprotection, MESH: Cysteine Proteinase Inhibitors, 03 medical and health sciences, Cellular and Molecular Neuroscience, Internal medicine, medicine, Animals, Nerve Growth Factors, 030304 developmental biology, Amyloid beta-Peptides, MESH: Caspases, MESH: Nerve Growth Factors, MESH: Apoptosis, Neuropeptides, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, Neurotoxicity, Granule cell, medicine.disease, Peptide Fragments, MESH: Cerebellum, Rats, biology.protein, Granule cells, 030217 neurology & neurosurgery
Abstract

International audience; The beta-amyloid (Abeta) peptide Abeta25-35 provokes apoptosis of cerebellar granule cells through activation of caspase-3 while the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) promotes granule cell survival by inhibiting caspase-3 activation through the intrinsic apoptotic pathway. The aim of the present study was to determine whether PACAP could prevent Abeta25-35 neurotoxicity by inhibiting caspase-3 activity. A 24-h exposure of cultured cerebellar granule cells to Abeta25-35 induced shrinkage of cell bodies, neurite retraction and alteration of mitochondrial activity. Administration of graded concentrations (10-80 microM) of Abeta25-35 induced a dose-related decrease of the number of living cells, and the neurotoxic effect was highly significant after a 24-h exposure to 80 microM Abeta25-35. Exposure of cerebellar granule cells to Abeta25-35 markedly enhanced caspase-3 but not caspase-9 activity. Co-incubation with 1 microM PACAP significantly reduced Abeta25-35-evoked caspase-3 activation. In contrast, PACAP did not prevent the deleterious effects of Abeta25-35 on mitochondrial potential and granule cell survival. Taken together, these data suggest that caspase-3 activation is not the main pathway activated by Abeta25-35 that leads to granule cell death. The results also demonstrate that PACAP cannot be considered as a potent neuroprotective factor against Abeta25-35-induced apoptosis in cerebellar granule neurons.

Published
2004
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5. Pituitary Adenylate Cyclase-Activating Polypeptide Reverses Ammonium Metavanadate-Induced Airway Hyperresponsiveness in Rats

Author

Sonia Rouatbi, David Vaudry, Badreddine Sriha, Khémais Ben Rhouma, Olivier Wurtz, Mounira Tlili, Olfa Tebourbi, Mohsen Sakly, Laboratoire d'Informatique, de Parallélisme et de Productique (LIP2), Faculté des Sciences Mathématiques, Physiques et Naturelles de Tunis (FST), Université de Tunis El Manar (UTM)-Université de Tunis El Manar (UTM), Université de Sousse, Faculté des Sciences de Bizerte [Université de Carthage], Université de Carthage - University of Carthage, Physiologie Intégrée, Université de Carthage - University of Carthage-Université de Carthage - University of Carthage, International Associated laboratory Samuel de Champlain, Institut National de la Recherche Scientifique [Québec] (INRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), and Université de Rouen Normandie (UNIROUEN)

Subjects
Male, Aging, Chemokine, MESH: Macrophages, Alveolar, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Chemokine CXCL2, Environmental pollution, medicine.disease_cause, Biochemistry, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, chemistry.chemical_compound, MESH: Aerosols, Interleukin-1alpha, MESH: Animals, Respiratory system, MESH: Interleukin-1alpha, Lung, Chemokine CCL3, MESH: Oxidative Stress, biology, Chemistry, lcsh:Cytology, MESH: Real-Time Polymerase Chain Reaction, General Medicine, MESH: Administration, Inhalation, 3. Good health, MESH: Respiratory Hypersensitivity, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Pituitary Adenylate Cyclase-Activating Polypeptide, Tumor necrosis factor alpha, Research Article, medicine.medical_specialty, Article Subject, MESH: Rats, Adenylate kinase, Real-Time Polymerase Chain Reaction, Proinflammatory cytokine, Ammonium metavanadate, Internal medicine, Administration, Inhalation, Macrophages, Alveolar, medicine, Respiratory Hypersensitivity, MESH: Chemokine CXCL2, Animals, MESH: Lung, MESH: Chemokine CCL3, lcsh:QH573-671, Rats, Wistar, Aerosols, Tumor Necrosis Factor-alpha, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, Cell Biology, MESH: Rats, Wistar, MESH: Male, Rats, Oxidative Stress, Endocrinology, MESH: Vanadates, 13. Climate action, MESH: Tumor Necrosis Factor-alpha, biology.protein, Vanadates, Oxidative stress
Abstract

The rate of atmospheric vanadium is constantly increasing due to fossil fuel combustion. This environmental pollution favours vanadium exposure in particular to its vanadate form, causing occupational bronchial asthma and bronchitis. Based on the well admitted bronchodilator properties of the pituitary adenylate cyclase-activating polypeptide (PACAP), we investigated the ability of this neuropeptide to reverse the vanadate-induced airway hyperresponsiveness in rats. Exposure to ammonium metavanadate aerosols (5 mg/m3/h) for 15 minutes induced 4 hours later an array of pathophysiological events, including increase of bronchial resistance and histological alterations, activation of proinflammatory alveolar macrophages, and increased oxidative stress status. Powerfully, PACAP inhalation (0.1 mM) for 10 minutes alleviated many of these deleterious effects as demonstrated by a decrease of bronchial resistance and histological restoration. PACAP reduced the level of expression of mRNA encoding inflammatory chemokines (MIP-1α, MIP-2, and KC) and cytokines (IL-1αand TNF-α) in alveolar macrophages and improved the antioxidant status. PACAP reverses the vanadate-induced airway hyperresponsiveness not only through its bronchodilator activity but also by counteracting the proinflammatory and prooxidative effects of the metal. Then, the development of stable analogs of PACAP could represent a promising therapeutic alternative for the treatment of inflammatory respiratory disorders.

Published
2014
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6. Design and characterization of novel cell-penetrating peptides from pituitary adenylate cyclase-activating polypeptide

Author

Hubert Vaudry, David Vaudry, Ngoc-Duc Doan, Myriam Létourneau, Nicolas Doucet, David Chatenet, Benjamin Folch, Alain Fournier, Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), International Associated laboratory Samuel de Champlain, Institut National de la Recherche Scientifique [Québec] (INRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), and This work was supported by the CIHR grant #102734 (Alain Fournier) and NSERC Discovery grant GPIN 402623-2011 (Nicolas Doucet). Nicolas Doucet also acknowledges supports from the FRQNT Strategic Cluster 'Regroupement Québécois de Recherche sur la Fonction, la Structure et l'Ingénierie des Protéines' (PROTEO) and the FRQS Strategic Cluster 'Groupe de Recherche Axé sur la Structure des Protéines' (GRASP).

Subjects
media_common.quotation_subject, Green Fluorescent Proteins, Endogenous cell-penetrating peptide, Pharmaceutical Science, MESH: Cricetinae, CHO Cells, Cell-Penetrating Peptides, MESH: Drug Design, Endocytosis, PACAP, Transfection, 03 medical and health sciences, 0302 clinical medicine, MESH: Green Fluorescent Proteins, Cricetulus, MESH: Cricetulus, MESH: CHO Cells, MESH: Plasmids, Cellular uptake, Cricetinae, Animals, Humans, MESH: Animals, Internalization, 030304 developmental biology, media_common, MESH: Cell-Penetrating Peptides, 0303 health sciences, MESH: Humans, Chemistry, Pinocytosis, MESH: Transfection, HEK 293 cells, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, In vitro, HEK293 Cells, Biochemistry, Lipofectamine, MESH: HEK293 Cells, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Drug Design, Drug delivery, Pituitary Adenylate Cyclase-Activating Polypeptide, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery, Intracellular, Plasmids
Abstract

International audience; The discovery of cell-penetrating peptide opened up new promising avenues for the non-invasive delivery of non-permeable biomolecules within the intracellular compartment. However, some setbacks such as possible toxic effects or unexpected immunological responses have limited their use in clinic. To overcome these obstacles, we investigated the use of novel cell-penetrating peptides (CPPs) derived from the endogenous neuropeptide Pituitary adenylate cyclase-activating polypeptide (PACAP). First, we demonstrated the propensity of native PACAP isoforms (PACAP27 and PACAP38) to efficiently deliver a large and non-permeable molecule, i.e. streptavidin, into cells. An inactive modified fragment of PACAP38, i.e. [Arg(17)]PACAP(11-38), with preserved cell-penetrating physico-chemical properties, was also synthesized and successfully use for the intracellular delivery of various cargoes such as small molecules, peptides, proteins, and polynucleotides. Especially, its effectiveness as a transfection agent was comparable to Lipofectamine 2000 while being non-toxic for cells. Uptake mechanism studies demonstrated that direct translocation, caveolae-dependent endocytosis and macropinocytosis were involved in the internalization of [Arg(17)]PACAP(11-38). This study not only opened up a new aspect in the usefulness of PACAP and its derivatives for therapeutic application but also contributed to the identification of new members of the CPP family. As such, inactive PACAP-related analogs could represent excellent vectors for in vitro and in vivo applications.

Published
2012
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7. Receptor-independent cellular uptake of pituitary adenylate cyclase-activating polypeptide

Author

Myriam Létourneau, Ngoc-Duc Doan, Hubert Vaudry, Alain Fournier, David Chatenet, David Vaudry, Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Université Laval [Québec] (ULaval), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Financial support was obtained from the CIHR

Subjects
Male, Intracrine, Transcription, Genetic, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Amino Acid Sequence, MESH: Rats, Sprague-Dawley, MESH: Protein Isoforms, Mass Spectrometry, Rats, Sprague-Dawley, 0302 clinical medicine, Cytosol, MESH: Cytosol, Testis, Protein Isoforms, MESH: Animals, Receptor, 0303 health sciences, MESH: Testis, Pinocytosis, Intracellular receptor, Endocytosis, Biochemistry, MESH: Cell Survival, MESH: Calcium, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Intranuclear calcium release, MESH: Endocytosis, Pituitary Adenylate Cyclase-Activating Polypeptide, Intracellular, hormones, hormone substitutes, and hormone antagonists, Fluorescein-5-isothiocyanate, Protein Binding, MESH: Cell Nucleus, endocrine system, MESH: Rats, Cell Survival, Molecular Sequence Data, Adenylate kinase, Translocation, Biology, Cell Line, 03 medical and health sciences, MESH: Fluorescein-5-isothiocyanate, MESH: Protein Binding, Animals, Humans, Amino Acid Sequence, Molecular Biology, 030304 developmental biology, MESH: Mass Spectrometry, Cell Nucleus, MESH: Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Humans, MESH: Molecular Sequence Data, Binding Sites, MESH: Transcription, Genetic, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, Cell Membrane, Cell Biology, MESH: Male, MESH: Cell Line, Rats, Nuclear receptor, MESH: Binding Sites, Intracrine factor, Calcium, 030217 neurology & neurosurgery, MESH: Cell Membrane
Abstract

International audience; Pituitary adenylate cyclase-activating polypeptide (PACAP), a hypophysiotropic neurohormone, participates in the regulation of pleiotropic functions. The recent discovery of intracellular PACAP receptors in the brain and the testis as well as the physico-chemical characteristics of PACAP, i.e. extended α-helix containing basic residues, prompted us to evaluate the propensity of PACAP to cross the plasma membrane in a receptor-independent manner. Using confocal microscopy and flow cytometry, we demonstrated the ability of FITC-conjugated PACAP to efficiently penetrate into the internal cell compartment by direct translocation and endocytosis through clathrin-coated pits and macropinocytosis. Our study also revealed that, once inside the cells, PACAP38 is not entirely degraded by intracellular enzymes and that a significant amount of intact PACAP38 is also able to exit cells. Moreover, using binding assay on rat nuclear fractions from various tissues, PACAP nuclear receptors were identified. We also found that PACAP stimulates calcium release in rat testis nuclei. Interestingly, PACAP27 and PACAP38 but not VIP were able to upregulate de novo DNA synthesis in testis nuclei and that this effect was abolished by PACAP(6-38). These results support the presence of PAC1 receptors at the nuclear membrane and raise questions about their role in the biological activity of the peptide. These findings contribute to the characterization of PACAP as an intracrine factor and suggest that these intracellular PAC1 binding sites, probably associated with specific biological activities, should be taken into account during the development of PACAP-based drugs.

Published
2011
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8. Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates the expression and the release of tissue plasminogen activator (tPA) in neuronal cells: involvement of tPA in the neuroprotective effect of PACAP

Author

Raoult, Emilie, Roussel, Benoît Denis, Bénard, Magalie, Lefebvre, Thomas, Ravni, Aurélia, Ali, Carine, Vivien, Denis, Komuro, Hitoshi, Fournier, Alain, Vaudry, Hubert, Vaudry, David, Galas, Ludovic, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), International Associated laboratory Samuel de Champlain, Institut National de la Recherche Scientifique [Québec] (INRS)-Université de Rouen Normandie (UNIROUEN), Sérine protéases et physiopathologie de l'unité neurovasculaire, Université de Caen Normandie (UNICAEN), Department of Neuroscience/NC30, Cleveland Clinic-Lerner Research Institute, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), and This work was supported by INSERM, the European Institute for Peptide Research (IFRMP23), the Cell Imaging Platform of Normandy (PRIMACEN), the FEDER program # 2517, the Interreg 4A TC2N project, the LARC-Neurosciences Network and the Région Haute-Normandie

Subjects
Male, endocrine system, MESH: Rats, Cell Survival, MESH: Neurons, Real-Time Polymerase Chain Reaction, PC12 Cells, Gene Expression Regulation, Enzymologic, Cell Movement, MESH: Tissue Plasminogen Activator, Cerebellum, MESH: PC12 Cells, Animals, MESH: Animals, cerebellar granule neurons, Enzyme Inhibitors, Rats, Wistar, MESH: Cell Movement, Neurons, integumentary system, MESH: Culture Media, Conditioned, MESH: Real-Time Polymerase Chain Reaction, MESH: Gene Expression Regulation, Enzymologic, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Neuroprotective Agents, MESH: Rats, Wistar, MESH: Cerebellum, MESH: Male, Rats, Neuroprotective Agents, MESH: Cell Survival, MESH: Enzyme Inhibitors, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Culture Media, Conditioned, Tissue Plasminogen Activator, Pituitary Adenylate Cyclase-Activating Polypeptide, neuroprotection, Female, MESH: Female, hormones, hormone substitutes, and hormone antagonists
Abstract

International audience; Pituitary adenylate cyclase-activating polypeptide (PACAP) and tissue plasminogen activator (tPA) play important roles in neuronal migration and survival. However, a direct link between the neurotrophic effects of PACAP and tPA has never been investigated. In this study, we show that, in PC12 cells, PACAP induced a 9.85-fold increase in tPA gene expression through activation of the protein kinase A- and protein kinase C-dependent signaling pathways. In immature cerebellar granule neurons (CGN), PACAP stimulated tPA mRNA expression and release of proteolytically active tPA. Immunocytochemical labeling revealed the presence of tPA in the cytoplasm and processes of cultured CGN. The inhibitory effect of PACAP on CGN motility was not affected by the tPA substrate plasminogen or the tPA inhibitor plasminogen activator inhibitor-1. In contrast, plasminogen activator inhibitor-1 significantly reduced the stimulatory effect of PACAP on CGN survival. Altogether, these data indicate that tPA gene expression is activated by PACAP in both tumoral and normal neuronal cells. The present study also demonstrates that PACAP stimulates the release of tPA which promotes CGN survival by a mechanism dependent of its proteolytic activity.

Published
2011
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9. Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects

Author

Michel Detheux, Agnieszka Dejda, David Vaudry, David Chatenet, Alain Fournier, Steve Bourgault, Hubert Vaudry, Myriam Létourneau, Ngoc-Duc Doan, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), International Associated laboratory Samuel de Champlain, Institut National de la Recherche Scientifique [Québec] (INRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Euroscreen S.A., Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), and This work was supported by the Canadian Institutes of Health Research

Subjects
Agonist, medicine.drug_class, Receptors, Vasoactive Intestinal Polypeptide, Type I, MESH: Neurons, MESH: Cricetinae, CHO Cells, MESH: Drug Design, Pharmacology, Biology, Transfection, Biochemistry, Neuroprotection, Calcium in biology, 03 medical and health sciences, Structure-Activity Relationship, MESH: Structure-Activity Relationship, 0302 clinical medicine, Cricetulus, MESH: Cricetulus, MESH: CHO Cells, Cricetinae, medicine, Animals, Humans, MESH: Animals, Receptor, 030304 developmental biology, Neurons, 0303 health sciences, MESH: Humans, MESH: Transfection, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, Dopaminergic, Rational design, MESH: Receptors, Vasoactive Intestinal Polypeptide, Type I, MESH: Neuroprotective Agents, In vitro, 3. Good health, Pituitary adenylate cyclase-activating peptide, Neuroprotective Agents, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Drug Design, MESH: Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I, Pituitary Adenylate Cyclase-Activating Polypeptide, 030217 neurology & neurosurgery, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Abstract

International audience; Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide that exerts a large array of actions in the central nervous system and periphery. Through the activation of PAC1 and VPAC1, PACAP is able to exert neuroprotective, as well as anti-inflammatory effects, two phenomena involved in the pathogenesis and the progression of neurodegenerative diseases. The aim of the current study was to provide insights into the molecular arrangement of the amino terminus of PACAP and to develop new potent and selective PAC1/VPAC1 agonists promoting neuronal survival. We have synthesized a series of PACAP derivatives and measured their binding affinity and their ability to induce intracellular calcium mobilization for each receptor, i.e. PAC1, VPAC1, and VPAC2. Ultimately, analogs with an improved pharmacological profile were evaluated in an in vitro model of neuronal loss. Results showed that introduction of a hydroxyproline or an alanine moiety, respectively, at position 2 or 7 generated derivatives without significant VPAC2 agonistic activity. Moreover, the structure-activity relationship study suggests the presence of common (Asx-turn like) and distinct (different N-capping type) secondary structures that might be responsible for receptor recognition, selectivity and activation. Finally, evaluation of the neuroprotective activity of [Ala(7)]PACAP27 and [Hyp(2)]PACAP27 demonstrated their ability to protect potently human dopaminergic SH-SY5Y neuroblasts against the toxicity of MPP(+), in pre- and co-treatment experiments. These new pharmacological and structural data should prove useful for the rational design of PACAP-derived compounds that could be putative therapeutic agents for the treatment of neurodegenerative diseases.

Published
2010
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10. Balanced effect of PACAP and FasL on granule cell death during cerebellar development: a morphological, functional and behavioural characterization

Author

Emma R. Isaac, Bruno J. Gonzalez, Delphine Burel, Ludovic Galas, Alain Fournier, Pierre Chapillon, Nancy M. Sherwood, Bénédicte Parent, Vincent Roy, Sébastien Arthaud, Hubert Vaudry, Arnaud Desfeux, Aurélie Allais, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Institute for Research and Innovation in Biomedicine (IRIB), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Biology, University of Victoria [Canada] (UVIC), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Armand Frappier (INRS-IAF), and Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)

Subjects
MESH: Cell Death, Cerebellum, Time Factors, MESH: Neurons, Biochemistry, MESH: Mice, Knockout, Fas ligand, MESH: Animals, Newborn, Mice, 0302 clinical medicine, MESH: Gene Expression Regulation, Developmental, MESH: Behavior, Animal, MESH: Caspase 3, MESH: Animals, Caspase, MESH: Cell Size, MESH: Bromodeoxyuridine, Mice, Knockout, Neurons, 0303 health sciences, MESH: Muscle, Skeletal, MESH: Statistics, Nonparametric, biology, Behavior, Animal, Cell Death, Caspase 3, Gene Expression Regulation, Developmental, MESH: Motor Activity, Pituitary adenylate cyclase-activating peptide, medicine.anatomical_structure, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Pituitary Adenylate Cyclase-Activating Polypeptide, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, Programmed cell death, endocrine system, Fas Ligand Protein, MESH: Reflex, MESH: Psychomotor Performance, In Vitro Techniques, Motor Activity, Statistics, Nonparametric, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Mice, Inbred C57BL, Internal medicine, MESH: Cell Proliferation, Reflex, medicine, Animals, RNA, Messenger, Muscle, Skeletal, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Cell Proliferation, Cell Size, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Time Factors, Granule cell, MESH: Cerebellum, MESH: Fas Ligand Protein, Mice, Inbred C57BL, Endocrinology, Animals, Newborn, Bromodeoxyuridine, Apoptosis, biology.protein, 030217 neurology & neurosurgery, Psychomotor Performance
Abstract

International audience; It is now established that the development of the CNS requires equilibrium between cell survival and apoptosis. Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts a powerful protective effect on cerebellar granule cells by inhibiting the caspase 3. In contrast, Fas ligand (FasL) plays an essential role during ontogenesis in eliminating supernumerary neurons by apoptosis. To determine if PACAP and FasL interact during cerebellar development, we characterized the effects of these factors on cerebellar morphogenesis and caspase 3 activity in PACAP+/+ and PACAP-/- mice. First, we demonstrated in vivo that PACAP is able to reverse the diminution of internal granule cell layer thickness induced by FasL in PACAP+/+ and PACAP-/- mice. Second, ex vivo and immunohistochemical studies revealed that interaction between FasL and PACAP occurs through the caspase 3 activity. Third, behavioural study showed a significant difference for the PACAP + FasL group in the righting reflex test at P8 which does not persist at P60. Finally, a time course study revealed that the pro-apoptotic effect of FasL characterized at P8 was followed by a progressive compensatory mechanism in caspase 3 activity and bromodeoxyuridine incorporation. These data suggest that PACAP and FasL interact during cerebellar development to control apoptosis of granule cells and may affect some motor cerebellar functions.

Published
2010
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11. Biological and structural analysis of truncated analogs of PACAP27

Author

Hubert Vaudry, Emilie Raoult, Steve Bourgault, Alain Couvineau, Laure Guilhaudis, Alain Fournier, Isabelle Ségalas-Milazzo, David Vaudry, Marc Laburthe, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), International Associated laboratory Samuel de Champlain, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Scientifique [Québec] (INRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and This work was supported by the Agence Nationale de la Recherche (ANR), the Institut National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale (INSERM U413), the Conseil Régional de Haute-Normandie, and a scientific exchange program from INSERM and the Fonds de la Recherche en Santé du Québec. Parts of these studies were performed with the support of the Platform for Cell Imaging of Haute-Normandie. H.V. is an Affiliated Professor at the Institut National de la Recherche Scientifique--Institut Armand-Frappier.

Subjects
Circular dichroism, MESH: Rats, Molecular Sequence Data, MESH: Cricetinae, MESH: Amino Acid Sequence, CHO Cells, PAC1 Receptor, PC12 Cells, MESH: Circular Dichroism, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Cricetulus, MESH: Cricetulus, MESH: CHO Cells, MESH: Cell Proliferation, Cricetinae, MESH: PC12 Cells, Animals, MESH: Animals, Amino Acid Sequence, Receptor, MESH: Peptide Fragments, Peptide sequence, 030304 developmental biology, Cell Proliferation, 0303 health sciences, MESH: Molecular Sequence Data, biology, Chemistry, Cell growth, Chinese hamster ovary cell, Circular Dichroism, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, Biological activity, General Medicine, biology.organism_classification, Peptide Fragments, Rats, Biochemistry, [SDV.TOX]Life Sciences [q-bio]/Toxicology, MESH: Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I, Biophysics, Pituitary Adenylate Cyclase-Activating Polypeptide, 030217 neurology & neurosurgery, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Abstract

International audience; The affinity toward the PAC1 receptor, the biological activity, and the alpha-helical content of several truncated PACAP27 analogs were measured. We first evaluated the pharmacological and structural parameters of C-terminal shortened PACAP fragments, from PACAP(1-23) to PACAP(1-19). All carboxy-truncated derivatives demonstrated circular dichroism spectra typical of a helical conformation. On the other hand, progressive shortening of the C-terminal domain gradually decreases the potency of PACAP to bind and to activate the PAC1 receptor. This decrease in biological activity was mainly attributed to the removal of residues that seem to interact directly with the receptor rather than to a destabilization of the C-terminal helical conformation. We also investigated the pharmacological and conformational characteristics of several hybrid PACAP27 derivatives containing an aliphatic molecular spacer connecting the N-terminal domain to the C-terminal region. However, this strategy revealed that none of these discontinuous analogs showed any significant affinity toward the PAC1 receptor, even if some of them exhibited circular dichroism spectra corresponding to an alpha-helical structure. This study suggests that several domains of PACAP27 are involved in the interaction with the PAC1 receptor and that the presence of the helical conformation is not a sufficient feature for receptor activation.

Published
2008
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12. Selenoprotein T is a PACAP-regulated gene involved in intracellular Ca2+ mobilization and neuroendocrine secretion

Author

Nathalie C. Guérineau, Alain Fournier, Didier Vieau, Hubert Vaudry, Youssef Anouar, Stéphane Gasman, Abdel G. Elkahloun, Luca Grumolato, Djida Ait-Ali, Jean Lesage, Ludovic Galas, Hafida Ghzili, Yannick Tanguy, Maité Montero-Hadjadje, Jérôme Leprince, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Neurotransmission et sécrétion neuroendocrine (NSN), Centre National de la Recherche Scientifique (CNRS), Environnement périnatal et croissance - EA 4489 (EPS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancer Genetics Branch, National Institute of Health (NIH)-National Human Genome Research Institute (NHGRI), Montreal Heart Institute (MONTREAL HEART INSTITUTE), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cellular differentiation, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Endoplasmic Reticulum, Biochemistry, PC12 Cells, MESH: Selenoproteins, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Gene expression, Cyclic AMP, MESH: Animals, Selenoproteins, MESH: Cyclic AMP, Regulation of gene expression, chemistry.chemical_classification, 0303 health sciences, Gene knockdown, Neurosecretion, 030302 biochemistry & molecular biology, Selenoprotein T, Cell Differentiation, MESH: Gene Expression Regulation, MESH: Calcium, Pituitary Adenylate Cyclase-Activating Polypeptide, Biotechnology, MESH: Cell Differentiation, MESH: Selenocysteine, MESH: Rats, MESH: Neurosecretion, Biology, MESH: Calcium Signaling, 03 medical and health sciences, MESH: Endoplasmic Reticulum, Genetics, MESH: PC12 Cells, Animals, Secretion, Calcium Signaling, Molecular Biology, 030304 developmental biology, Endoplasmic reticulum, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, Molecular biology, Rats, Selenocysteine, chemistry, Gene Expression Regulation, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Calcium, Selenoprotein
Abstract

International audience; Selenoproteins contain the essential trace element selenium, the deficiency of which is associated with cancer or accelerated aging. Although selenoproteins are thought to be instrumental for the effects of selenium, the biological function of many of these proteins remains unknown. Here, we studied the role of selenoprotein T (SelT), a selenocysteine (Sec) -containing protein with no known function, which we have identified as a novel target gene of the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) during PC12 cell differentiation. SelT was found to be ubiquitously expressed throughout embryonic development and in adulthood in rat. Immunocytochemical analysis revealed that SelT is mainly localized to the endoplasmic reticulum through a hydrophobic domain. PACAP and cAMP induced a rapid and long-lasting increase in SelT gene expression in PC12 cells, in a Ca(2+)-dependent manner. These results suggested a possible role of SelT in PACAP signaling during PC12 cell differentiation. Indeed, overexpression of SelT in PC12 cells provoked an increase in the concentration of intracellular Ca(2+) ([Ca(2+)](i)) that was dependent on the Sec residue. Conversely, SelT gene knockdown inhibited the PACAP-induced increase in [Ca(2+)](i) and reduced hormone secretion. These findings demonstrate the implication of a selenoprotein in the regulation of Ca(2+) homeostasis and neuroendocrine secretion in response to a cAMP-stimulating trophic factor.

Published
2008
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13. Actions of PACAP and VIP on melanotrope cells of Xenopus laevis

Author

Kidane, Adhanet, Cruijsen, Peter, Ortiz-Bazan, Maria, Vaudry, Hubert, Leprince, Jérôme, Kuijpers-Kwant, Frouwke, Roubos, Eric, Jenks, Bruce, Cruijsen, Peter M.J.M., Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Différenciation et communication neuronale et neuroendocrine (DC2N)

Subjects
Pro-Opiomelanocortin, Physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Vasoactive intestinal peptide, Xenopus, Gene Expression, Enteroendocrine cell, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biochemistry, MESH: Dose-Response Relationship, Drug, Xenopus laevis, 0302 clinical medicine, Endocrinology, MESH: Pituitary Gland, MESH: Reverse Transcriptase Polymerase Chain Reaction, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Pro-Opiomelanocortin, MESH: Animals, Receptor, Regulation of gene expression, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, MESH: Vasoactive Intestinal Peptide, Pars intermedia, Immunohistochemistry, 3. Good health, Pituitary adenylate cyclase-activating peptide, Pituitary Gland, Pituitary Adenylate Cyclase-Activating Polypeptide, hormones, hormone substitutes, and hormone antagonists, Vasoactive Intestinal Peptide, medicine.medical_specialty, endocrine system, MESH: Gene Expression, Melanotrophs, Neurophysiology, Neuropeptide, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Xenopus laevis, Internal medicine, medicine, Animals, 030304 developmental biology, Dose-Response Relationship, Drug, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Immunohistochemistry, biology.organism_classification, MESH: Melanotrophs, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030217 neurology & neurosurgery
Abstract

Item does not contain fulltext The neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are implicated in the regulation of gene expression and hormone secretion in mammalian melanotrope cells and a mammalian pro-opiomelanocortin (POMC)-producing tumor cell line, but the physiological relevance of this regulation is elusive. The purpose of the present study was to establish if these peptides affect biosynthetic and secretory processes in a well-established physiological model for endocrine cell functioning, the pituitary melanotrope cells of the amphibian Xenopus laevis, which hormonally control the process of skin color adaptation to background illumination. We show that both PACAP and VIP are capable of stimulating the secretory process of the Xenopus melanotrope cell. As the peptides are equipotent, they may exert their actions via a VPAC receptor. Moreover, PACAP stimulated POMC biosynthesis and POMC gene expression. Strong anti-PACAP immunoreactivity was found in the pituitary pars nervosa (PN), suggesting that this neurohemal organ is a source of neurohormonal PACAP action on the melanotropes in the intermediate pituitary. We propose that the PACAP/VIP family of peptides has a physiological function in regulating Xenopus melanotrope cell activity during the process of skin color adaptation.

Published
2007
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14. PACAP stimulates biosynthesis and release of endozepines from rat astrocytes

Author

Marie-Christine Tonon, Georges Pelletier, David Vaudry, Pierrick Gandolfo, Olfa Masmoudi-Kouki, Alain Fournier, Hubert Vaudry, Jérôme Leprince, Faculty of Sciences of Tunis (University of Tunis), Université de Tunis El Manar (UTM), Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Laval University Medical center, Université Laval [Québec] (ULaval), Institut Armand Frappier (INRS-IAF), and Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)

Subjects
MESH: Signal Transduction, medicine.medical_specialty, endocrine system, Endozepine, MESH: Rats, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Vasoactive intestinal peptide, Neuropeptide, MESH: Adenylyl Cyclases, MESH: Cyclic AMP-Dependent Protein Kinases, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, General Biochemistry, Genetics and Molecular Biology, Adenylyl cyclase, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, History and Philosophy of Science, Downregulation and upregulation, Internal medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Animals, MESH: Animals, Receptor, Protein kinase C, Cells, Cultured, 030304 developmental biology, Diazepam Binding Inhibitor, 0303 health sciences, Chemistry, General Neuroscience, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, Cyclic AMP-Dependent Protein Kinases, 3. Good health, Rats, MESH: Astrocytes, medicine.anatomical_structure, Endocrinology, Astrocytes, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Diazepam Binding Inhibitor, Pituitary Adenylate Cyclase-Activating Polypeptide, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, Astrocyte, MESH: Cells, Cultured, Adenylyl Cyclases, Signal Transduction
Abstract

International audience; Astrocytes synthesize and release endozepines, a family of neuropeptides related to diazepam-binding inhibitor (DBI). Astroglial cells also express the receptors of pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). In the present article, we show that PACAP dose dependently increases DBI gene expression and stimulates endozepine release through activation of PAC1-R. PACAP increases cAMP formation, enhances polyphosphoinositide turnover, and evokes calcium mobilization from intracellular Ca2+ pools. The effect of PACAP on endozepine release is mediated through the adenylyl cyclase/PKA pathway while the downregulation of astrocyte response to PACAP can be ascribed to activation of the PLC/PKC pathway.

Published
2006
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15. Opposite regulation of the mitochondrial apoptotic pathway by C2-ceramide and PACAP through a MAP-kinase-dependent mechanism in cerebellar granule cells

Author

Falluel-Morel, Anthony, Aubert, Nicolas, Vaudry, David, Basille, Magali, Fontaine, Marc, Fournier, Alain, Vaudry, Hubert, Gonzalez, Bruno J, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Defense Proteins in Immune and Inflammatory Responses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Faculty of Medicine and Pharmacy-European Institute for Peptide Research-Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), and This research was supported by an INSERM Grant (U413) and an IREB Grant (2001/22). AFM is recipient of a fellowship from the Conseil Re ́gional de Haute-Normandie (LARC-Neuroscience net- work). NA is a recipient of a fellowship from the Conseil Régional de Haute-Normandie and the CIT-IFM Recherche.

Subjects
MESH: Signal Transduction, Time Factors, MAP Kinase Kinase 4, MESH: Drug Interactions, MESH: Neurons, Fluorescent Antibody Technique, MESH: Neurotransmitter Agents, MESH: Neuropeptides, MESH: Caspase 9, MESH: Animals, Newborn, MESH: Dose-Response Relationship, Drug, Membrane Potentials, Mice, Cytosol, MESH: Cytosol, Sphingosine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Cerebellum, MESH: Caspase 3, MESH: Animals, Drug Interactions, Enzyme Inhibitors, MESH: Fluorescent Antibody Technique, Cells, Cultured, bcl-2-Associated X Protein, Neurons, Neurotransmitter Agents, Caspase 3, Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, Cytochromes c, MESH: Cytochromes c, Carbocyanines, MESH: Gene Expression Regulation, Caspase 9, Mitochondria, ERK, Proto-Oncogene Proteins c-bcl-2, MESH: Enzyme Inhibitors, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Caspases, Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Carbocyanines, MESH: Sphingosine, Mitogen-Activated Protein Kinases, hormones, hormone substitutes, and hormone antagonists, MESH: MAP Kinase Kinase 4, MESH: Cells, Cultured, Signal Transduction, endocrine system, MESH: Rats, MESH: Mitochondria, Blotting, Western, Models, Neurological, MESH: Mitogen-Activated Protein Kinase Kinases, mitochondrial apoptotic pathway, MESH: Models, Neurological, MESH: Intracellular Signaling Peptides and Proteins, MESH: Membrane Potentials, MESH: Blotting, Western, Animals, Bcl-2, MESH: bcl-2-Associated X Protein, Nerve Growth Factors, RNA, Messenger, Rats, Wistar, MESH: Mice, MESH: RNA, Messenger, Mitogen-Activated Protein Kinase Kinases, MESH: Caspases, Dose-Response Relationship, Drug, MESH: Nerve Growth Factors, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Time Factors, Neuropeptides, JNK Mitogen-Activated Protein Kinases, MESH: JNK Mitogen-Activated Protein Kinases, MESH: Rats, Wistar, MESH: Mitogen-Activated Protein Kinases, MESH: Cerebellum, Rats, MESH: Proto-Oncogene Proteins c-bcl-2, Animals, Newborn, Gene Expression Regulation, Bax, Benzimidazoles, JNK, MESH: Benzimidazoles
Abstract

International audience; The sphingomyelin-derived messenger ceramides provoke neuronal apoptosis through caspase-3 activation, while the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) promotes neuronal survival and inhibits caspase-3 activity. However, the mechanisms leading to the opposite regulation of caspase-3 by C2-ceramide and PACAP are currently unknown. Here, we show that PACAP prevents C2-ceramide-induced inhibition of mitochondrial potential and C2-ceramide-evoked cytochrome c release. C2-ceramide stimulated Bax expression, but had no effect on Bcl-2, while PACAP abrogated the action of C2-ceramide on Bax and stimulated Bcl-2 expression. The effects of C2-ceramide and PACAP on Bax and Bcl-2 were blocked, respectively, by the JNK inhibitor L-JNKI1 and the MEK inhibitor U0126. L-JNKI1 prevented the alteration of mitochondria induced by C2-ceramide while U0126 suppressed the protective effect of PACAP against the deleterious action of C2-ceramide on mitochondrial potential. Moreover, L-JNKI1 inhibited the stimulatory effect of C2-ceramide on caspase-9 and -3 and prevented C2-ceramide-induced cell death. U0126 blocked PACAP-induced Bcl-2 expression, abrogated the inhibitory effect of PACAP on ceramide-induced caspase-9 activity, and promoted granule cell death. The present study reveals that C2-ceramide and PACAP exert opposite effects on Bax and Bcl-2 through, respectively, JNK- and ERK-dependent mechanisms. These data indicate that the mitochondrial pathway plays a pivotal role in the pro- and anti-apoptotic effects of C2-ceramide and PACAP.

Published
2004
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16. Strategies to Convert PACAP from a Hypophysiotropic Neurohormone Into a Neuroprotective Drug

Author

Ngoc-Duc Doan, Jérôme Leprince, Olivier Wurtz, Hubert Vaudry, David Chatenet, David Vaudry, Alain Fournier, Steve Bourgault, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), International Associated laboratory Samuel de Champlain, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Scientifique [Québec] (INRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Apoptosis, MESH: Receptors, G-Protein-Coupled, Pharmacology, Brain Ischemia, Receptors, G-Protein-Coupled, 0302 clinical medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Drug Discovery, MESH: Animals, media_common, 0303 health sciences, MESH: Cytokines, Microglia, MESH: Brain Ischemia, MESH: Neuroprotective Agents, 3. Good health, medicine.anatomical_structure, Neuroprotective Agents, MESH: Cell Survival, Cytokines, Pituitary Adenylate Cyclase-Activating Polypeptide, medicine.symptom, Intracellular, hormones, hormone substitutes, and hormone antagonists, Drug, endocrine system, Cell Survival, media_common.quotation_subject, Inflammation, Biology, Neuroprotection, 03 medical and health sciences, MESH: Drug Discovery, In vivo, medicine, Animals, Humans, Nerve Growth Factors, Neuroinflammation, 030304 developmental biology, MESH: Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Humans, MESH: Nerve Growth Factors, MESH: Apoptosis, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Astrocytes, Astrocytes, Brain Injuries, MESH: Brain Injuries, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030217 neurology & neurosurgery
Abstract

International audience; In neurological insults, such as cerebral ischemia and traumatic brain injury, complex molecular mechanisms involving inflammation and apoptosis are known to cause severe neuronal cell loss, emphasizing the necessity of developing therapeutic strategies targeting simultaneously these two processes. Over the last decade, numerous in vitro and in vivo studies have demonstrated the unique therapeutical potential of pituitary adenylate cyclase-activating polypeptide (PACAP) for the treatment of neuronal disorders involving apoptotic cell death and neuroinflammation. The neuroprotective activity of PACAP is based on its capacity to reduce the production of deleterious cytokines from activated microglia, to stimulate the release of neuroprotective agents from astrocytes and to inhibit pro-apoptotic intracellular pathways. However, the use of PACAP as a clinically applicable drug is hindered by its peptidic nature. As most natural peptides, native PACAP shows poor metabolic stability, low bioavailability, inadequate distribution and rapid blood clearance. Moreover, injection of PACAP to human can induce peripheral adverse side effects. Therefore, targeted chemical modifications and/or conjugation of PACAP to different macromolecules are required to improve the pharmacokinetic and pharmacological properties of PACAP. This review presents the chemical, biochemical and pharmacological strategies that are currently under development to convert PACAP from a hypophysiotropic neurohormone into a clinically relevant neuroprotective drug.

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