The sleep-modulating peptide orexin-B protects midbrain dopamine neurons from degeneration, alone or in cooperation with nicotine.

Content Provider	Semantic Scholar
Author	Guerreiro, Serge Florence, Clélia Rousseau, Erwann Hamadat, Sabah Hirsch, Etienne C. Michel, Patrick Pierre
Copyright Year	2015
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.
File Format	PDF HTM / HTML
DOI	10.1124/mol.114.095703
PubMed reference number	25552485
Journal	Medline
Volume Number	87
Issue Number	3
Alternate Webpage(s)	http://molpharm.aspetjournals.org/content/molpharm/87/3/525.full.pdf
Alternate Webpage(s)	https://doi.org/10.1124/mol.114.095703
Journal	Molecular pharmacology
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article