title: The sleep-modulating peptide orexin-B protects midbrain dopamine neurons from degeneration, alone or in cooperation with nicotine.
abstract: To determine whether orexinergic hypothalamic peptides can influence the survival of brainstem dopamine (DA) neurons, we used a model system of rat midbrain cultures in which DA neurons degenerate spontaneously and progressively as they mature. We established that orexin (OX)-B provides partial but significant protection to spontaneously dying DA neurons, whereas the homologous peptide OXA has only marginal effects. Importantly, DA neurons rescued by OXB accumulated DA efficiently by active transport, suggesting that they were functional. G-protein-coupled OX1 and OX2 receptors were both present on DA neurons, but the protective effect of OXB was attributable solely to OX2 receptors; a selective inhibitor of this receptor subtype, N-ethyl-2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), suppressed this effect, whereas a selective agonist, [Ala(11), d-Leu(15)]OXB, reproduced it. Survival promotion by OXB required intracellular calcium mobilization via inositol-1,4,5-triphosphate and ryanodine receptors. Nicotine, a well known neuroprotective molecule for DA neurons, improved OXB-mediated rescue through the activation of α-bungarotoxin-sensitive (presumably α7) nicotinic receptors, although nicotine had no effect on its own. Altogether, our data suggest that the loss of hypothalamic orexinergic neurons that occurs in Parkinson's disease might confer an increased vulnerability to midbrain DA neurons in this disorder.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, Université Pierre et Marie Curie, Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Guerreiro
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, Université Pierre et Marie Curie, Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Clélia
authors.initials: C
authors.lastname: Florence
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, Université Pierre et Marie Curie, Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Erwann
authors.initials: E
authors.lastname: Rousseau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, Université Pierre et Marie Curie, Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Sabah
authors.initials: S
authors.lastname: Hamadat
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, Université Pierre et Marie Curie, Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, Université Pierre et Marie Curie, Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Epinière, Paris, France patrick-pierre.michel@upmc.fr.
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Michel
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage*; D008636:Mesencephalon / Q000187:drug effects* / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control*; D009479:Neuropeptides / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009538:Nicotine / Q000008:administration & dosage*; D000068797:Orexins; D051381:Rats; D017208:Rats, Wistar; D012890:Sleep / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D000068797:Orexins; D009538:Nicotine