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2. Evaluation of the Spider (Phlogiellus genus) Phlotoxin 1 and Synthetic Variants as Antinociceptive Drug Candidates

Author

Tânia C. Gonçalves, Pierre Lesport, Sarah Kuylle, Enrico Stura, Justyna Ciolek, Gilles Mourier, Denis Servent, Emmanuel Bourinet, Evelyne Benoit, and Nicolas Gilles

Subjects
Phlogiellus spider, phlotoxin 1, human voltage-gated ion channel subtypes, NaV1.7 channel subtype, mouse model of NaV1.7-mediated pain, Medicine
Abstract

Over the two last decades, venom toxins have been explored as alternatives to opioids to treat chronic debilitating pain. At present, approximately 20 potential analgesic toxins, mainly from spider venoms, are known to inhibit with high affinity the NaV1.7 subtype of voltage-gated sodium (NaV) channels, the most promising genetically validated antinociceptive target identified so far. The present study aimed to consolidate the development of phlotoxin 1 (PhlTx1), a 34-amino acid and 3-disulfide bridge peptide of a Phlogiellus genus spider, as an antinociceptive agent by improving its affinity and selectivity for the human (h) NaV1.7 subtype. The synthetic homologue of PhlTx1 was generated and equilibrated between two conformers on reverse-phase liquid chromatography and exhibited potent analgesic effects in a mouse model of NaV1.7-mediated pain. The effects of PhlTx1 and 8 successfully synthetized alanine-substituted variants were studied (by automated whole-cell patch-clamp electrophysiology) on cell lines stably overexpressing hNaV subtypes, as well as two cardiac targets, the hCaV1.2 and hKV11.1 subtypes of voltage-gated calcium (CaV) and potassium (KV) channels, respectively. PhlTx1 and D7A-PhlTx1 were shown to inhibit hNaV1.1−1.3 and 1.5−1.7 subtypes at hundred nanomolar concentrations, while their affinities for hNaV1.4 and 1.8, hCaV1.2 and hKV11.1 subtypes were over micromolar concentrations. Despite similar analgesic effects in the mouse model of NaV1.7-mediated pain and selectivity profiles, the affinity of D7A-PhlTx1 for the NaV1.7 subtype was at least five times higher than that of the wild-type peptide. Computational modelling was performed to deduce the 3D-structure of PhlTx1 and to suggest the amino acids involved in the efficiency of the molecule. In conclusion, the present structure−activity relationship study of PhlTx1 results in a low improved affinity of the molecule for the NaV1.7 subtype, but without any marked change in the molecule selectivity against the other studied ion channel subtypes. Further experiments are therefore necessary before considering the development of PhlTx1 or synthetic variants as antinociceptive drug candidates.

Published
2019
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3. A Bacterial Toxin with Analgesic Properties: Hyperpolarization of DRG Neurons by Mycolactone

Author

Ok-Ryul Song, Han-Byul Kim, Samuel Jouny, Isabelle Ricard, Alexandre Vandeputte, Nathalie Deboosere, Estelle Marion, Christophe J. Queval, Pierre Lesport, Emmanuel Bourinet, Daniel Henrion, Seog Bae Oh, Guillaume Lebon, Guillaume Sandoz, Edouard Yeramian, Laurent Marsollier, and Priscille Brodin

Subjects
Buruli ulcer, mycolactone, AT2 receptors, DRG neurons, membrane potential, image-based assay, high-content screening, Medicine
Abstract

Mycolactone, a polyketide molecule produced by Mycobacterium ulcerans, is the etiological agent of Buruli ulcer. This lipid toxin is endowed with pleiotropic effects, presents cytotoxic effects at high doses, and notably plays a pivotal role in host response upon colonization by the bacillus. Most remarkably, mycolactone displays intriguing analgesic capabilities: the toxin suppresses or alleviates the pain of the skin lesions it inflicts. We demonstrated that the analgesic capability of mycolactone was not attributable to nerve damage, but instead resulted from the triggering of a cellular pathway targeting AT2 receptors (angiotensin II type 2 receptors; AT2R), and leading to potassium-dependent hyperpolarization. This demonstration paves the way to new nature-inspired analgesic protocols. In this direction, we assess here the hyperpolarizing properties of mycolactone on nociceptive neurons. We developed a dedicated medium-throughput assay based on membrane potential changes, and visualized by confocal microscopy of bis-oxonol-loaded Dorsal Root Ganglion (DRG) neurons. We demonstrate that mycolactone at non-cytotoxic doses triggers the hyperpolarization of DRG neurons through AT2R, with this action being not affected by known ligands of AT2R. This result points towards novel AT2R-dependent signaling pathways in DRG neurons underlying the analgesic effect of mycolactone, with the perspective for the development of new types of nature-inspired analgesics.

Published
2017
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4. The Emergent Role of Virtual Reality in the Treatment of Neuropsychiatric Disease

Author

Pierre Lesport, Amani Chassagneux, and Yacine Benyoucef

Subjects
Opinion, medicine.medical_specialty, 020205 medical informatics, 02 engineering and technology, Virtual reality, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, 0202 electrical engineering, electronic engineering, information engineering, Medicine, pain, Psychiatry, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, business.industry, General Neuroscience, neuropsychiatric disorder, rehabilitation medicine, cybertherapy, augmented reality, Neuropsychiatric disorder, virtual reality, Augmented reality, business, 030217 neurology & neurosurgery, Neuroscience, Neuropsychiatric disease
Published
2017
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5. A Bacterial Toxin with Analgesic Properties: Hyperpolarization of DRG Neurons by Mycolactone

Author

Christophe J. Queval, Isabelle Ricard, Seog Bae Oh, Priscille Brodin, Samuel Jouny, Edouard Yeramian, Alexandre Vandeputte, Han-Byul Kim, Pierre Lesport, Emmanuel Bourinet, Estelle Marion, Ok-Ryul Song, Nathalie Deboosere, Guillaume Sandoz, Daniel Henrion, Guillaume Lebon, Laurent Marsollier, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Department of Brain and Cognitive Sciences College of Natural Sciences [Seoul, Korea], Pain Cognitive Function Research Center [Seoul, Korea], Seoul National University [Seoul] (SNU)-Dental Research Institute [Seoul, Korea]-Seoul National University [Seoul] (SNU)-Dental Research Institute [Seoul, Korea], Department of Neurobiology and Physiology [Seoul, Korea], Seoul National University [Seoul] (SNU)-School of Dentistry [Seoul, Korea], ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Valrose (IBV), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Financial support for this work was provided by the European Community (ERC-STG INTRACELLTB Grant n°260901, MM4TB Grant n°260872), the Agence Nationale de Recherche (ANR-10-EQPX-04-01, ANR-14-CE14-0024, ANR-14-CE08-0017, ANR-11-LABX-0015-01), the Institut Pasteur of Lille, the FEDER (12001407 (D-AL) Equipex Imaginex BioMed), the Region Nord-Pas-de-Calais (convention n°12000080) and National Research Foundation (NRF) grant (2012R1A3A2048834 and 2016M3A9B6021209) funded by the Korean government (MEST), the Inserm Program ATIP avenir (granted to L.M., G.L. and G.S.), and the region Pays de la Loire (Kalmos project)., ANR-14-CE08-0017,ANTI-TB-NANO,Une galénique ' verte ' à base de nanoparticules de cyclodextrines pour un traitement plus efficace de la tuberculose(2014), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-14-CE14-0024,TB-MET,Rôle des métaux dans la virulence mycobactériennes et les défenses contre la tuberculose(2014), European Project: 260901,EC:FP7:ERC,ERC-2010-StG_20091118,INTRACELLTB(2010), European Project: 260872,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MM4TB(2011), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Dental Research Institute [Seoul, Korea]-Seoul National University [Seoul] (SNU)-Dental Research Institute [Seoul, Korea]-Seoul National University [Seoul] (SNU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), 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), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Université Nice Sophia Antipolis (... - 2019) (UNS), 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), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Bernardo, Elizabeth, Appel à projets générique - Une galénique ' verte ' à base de nanoparticules de cyclodextrines pour un traitement plus efficace de la tuberculose - - ANTI-TB-NANO2014 - ANR-14-CE08-0017 - Appel à projets générique - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Appel à projets générique - Rôle des métaux dans la virulence mycobactériennes et les défenses contre la tuberculose - - TB-MET2014 - ANR-14-CE14-0024 - Appel à projets générique - VALID, A Chemical Genomics Approach of Intracellular Mycobacterium tuberculosis Towards Defining Specific Host Pathogen Interactions - INTRACELLTB - - EC:FP7:ERC2010-12-01 - 2015-11-30 - 260901 - VALID, and More Medicines for Tuberculosis - MM4TB - - EC:FP7:HEALTH2011-02-01 - 2016-01-31 - 260872 - VALID

Subjects
0301 basic medicine, Buruli ulcer, Cell Survival, Health, Toxicology and Mutagenesis, Bacterial Toxins, lcsh:Medicine, mycolactone, [SDV.CAN]Life Sciences [q-bio]/Cancer, Toxicology, high-content screening, Receptor, Angiotensin, Type 2, Article, Membrane Potentials, AT2 receptors, DRG neurons, membrane potential, image-based assay, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Dorsal root ganglion, [SDV.CAN] Life Sciences [q-bio]/Cancer, Ganglia, Spinal, medicine, Mycolactone, Receptor, Neurons, Membrane potential, Analgesics, business.industry, AT 2 receptors, lcsh:R, Hyperpolarization (biology), medicine.disease, Angiotensin II, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, chemistry, Anesthesia, Macrolides, Signal transduction, business, 030217 neurology & neurosurgery
Abstract

Mycolactone, a polyketide molecule produced by Mycobacterium ulcerans, is the etiological agent of Buruli ulcer. This lipid toxin is endowed with pleiotropic effects, presents cytotoxic effects at high doses, and notably plays a pivotal role in host response upon colonization by the bacillus. Most remarkably, mycolactone displays intriguing analgesic capabilities: the toxin suppresses or alleviates the pain of the skin lesions it inflicts. We demonstrated that the analgesic capability of mycolactone was not attributable to nerve damage, but instead resulted from the triggering of a cellular pathway targeting AT2 receptors (angiotensin II type 2 receptors; AT2R), and leading to potassium-dependent hyperpolarization. This demonstration paves the way to new nature-inspired analgesic protocols. In this direction, we assess here the hyperpolarizing properties of mycolactone on nociceptive neurons. We developed a dedicated medium-throughput assay based on membrane potential changes, and visualized by confocal microscopy of bis-oxonol-loaded Dorsal Root Ganglion (DRG) neurons. We demonstrate that mycolactone at non-cytotoxic doses triggers the hyperpolarization of DRG neurons through AT2R, with this action being not affected by known ligands of AT2R. This result points towards novel AT2R-dependent signaling pathways in DRG neurons underlying the analgesic effect of mycolactone, with the perspective for the development of new types of nature-inspired analgesics.

Published
2017
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7. Systemic delivery of P42 peptide: a new weapon to fight Huntington's disease

Author

Christian Larroque, Yasmina Talmat-Amar, Caroline Bauer, Yoan Arribat, Alexia Paucard, Marie-Laure Parmentier, Florence Maschat, Pierre Lesport, Patrick Maurel, Nathalie Bonneaud, Lorraine Benigno, Nicole Bec, Taibi, Nadia, Emergence - Nouvelle stratégie thérapeutique contre la chorée de Huntington - - HuntToTreat2012 - ANR-12-EMMA-0013 - Emergence - VALID, 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), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medesis Pharma, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), ANR-12-EMMA-0013,HuntToTreat,Nouvelle stratégie thérapeutique contre la chorée de Huntington(2012), 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), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), and CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)

Subjects
Male, Huntingtin, Huntington ’ s disease, Nerve Tissue Proteins, Striatum, Pharmacology, Motor Activity, Bioinformatics, Pathology and Forensic Medicine, Mouse model, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, 0302 clinical medicine, Huntington's disease, Administration, Rectal, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, Neurons, 0303 health sciences, Huntingtin Protein, business.industry, Research, Administration, Buccal, Buccal administration, medicine.disease, Microemulsion, Corpus Striatum, Peptide Fragments, 3. Good health, Astrogliosis, Mice, Inbred C57BL, Disease Models, Animal, Huntington Disease, Rectal administration, Rotarod Performance Test, Drug delivery, Peptide, Cell-penetrating peptide, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), business, 030217 neurology & neurosurgery, HeLa Cells, Huntington’s disease
Abstract

Background In Huntington’s disease (HD), the ratio between normal and mutant Huntingtin (polyQ-hHtt) is crucial in the onset and progression of the disease. As a result, addition of normal Htt was shown to improve polyQ-hHtt-induced defects. Therefore, we recently identified, within human Htt, a 23aa peptide (P42) that prevents aggregation and polyQ-hHtt-induced phenotypes in HD Drosophila model. In this report, we evaluated the therapeutic potential of P42 in a mammalian model of the disease, R6/2 mice. Results To this end, we developed an original strategy for P42 delivery, combining the properties of the cell penetrating peptide TAT from HIV with a nanostructure-based drug delivery system (Aonys® technology), to form a water-in-oil microemulsion (referred to as NP42T) allowing non-invasive per mucosal buccal/rectal administration of P42. Using MALDI Imaging Mass Spectrometry, we verified the correct targeting of NP42T into the brain, after per mucosal administration. We then evaluated the effects of NP42T in R6/2 mice. We found that P42 (and/or derivatives) are delivered into the brain and target most of the cells, including the neurons of the striatum. Buccal/rectal daily administrations of NP42T microemulsion allowed a clear improvement of behavioural HD-associated defects (foot-clasping, rotarod and body weights), and of several histological markers (aggregation, astrogliosis or ventricular areas) recorded on brain sections. Conclusions These data demonstrate that NP42T presents an unprecedented protective effect, and highlight a new therapeutic strategy for HD, associating an efficient peptide with a powerful delivery technology. Electronic supplementary material The online version of this article (doi:10.1186/s40478-014-0086-x) contains supplementary material, which is available to authorized users.

Published
2013
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