title: Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson's disease.
abstract: To investigate whether the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) contributes to the death of dopamine neurons in Parkinson's disease, we undertook a genetic and a pharmacological approach using NOP receptor knockout (NOP(-/-)) mice, and the selective and potent small molecule NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). Stereological unbiased methods were used to estimate the total number of dopamine neurons in the substantia nigra of i) NOP(-/-) mice acutely treated with the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), ii) naïve mice subacutely treated with MPTP, alone or in combination with SB-612111, iii) rats injected with a recombinant adeno-associated viral (AAV) vector overexpressing human mutant p.A53T α-synuclein, treated with vehicle or SB-612111. NOP(-/-) mice showed a 50% greater amount of nigral dopamine neurons spared in response to acute MPTP compared to controls, which was associated with a milder motor impairment. SB-612111, given 4 days after MPTP treatment to mimic the clinical condition, prevented the loss of nigral dopamine neurons and striatal dopaminergic terminals caused by subacute MPTP. SB-612111, administered a week after the AAV injections in a clinically-driven protocol, also increased by 50% both the number of spared nigral dopamine neurons and striatal dopamine terminals, and prevented accompanying motor deficits induced by α-synuclein. We conclude that endogenous N/OFQ contributes to dopamine neuron loss in pathogenic and etiologic models of Parkinson's disease through NOP receptor-mediated mechanisms. NOP receptor antagonists might prove effective as disease-modifying agents in Parkinson's disease, through the rescue of degenerating nigral dopamine neurons and/or the protection of the healthy ones.
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy; Neuroscience Center and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors.forename: Ludovico
authors.initials: L
authors.lastname: Arcuri
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, Section of Human Physiology, University of Ferrara, via Fossato di Mortara 19, 44121 Ferrara, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Viaro
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy; Neuroscience Center and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Bido
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy; Neuroscience Center and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Longo
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy; Neuroscience Center and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Calcagno
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Fernagut
authors.affiliation: Astraea Therapeutics, 320 Logue Avenue, Mountain View, CA 94040, USA.
authors.forename: Nurulain T
authors.initials: NT
authors.lastname: Zaveri
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy; Neuroscience Center and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calò
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy; Neuroscience Center and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy. Electronic address: m.morari@unife.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
mesh_terms: D000818:Animals; D003508:Cycloheptanes / Q000008:administration & dosage; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D017353:Gene Deletion; D008124:Locomotion / Q000187:drug effects; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009292:Narcotic Antagonists / Q000008:administration & dosage; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010880:Piperidines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000094942:Nociceptin Receptor
chemical_list: D003508:Cycloheptanes; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; D000094942:Nociceptin Receptor
keywords: Adeno associated viral vectors; MPP(+); MPTP; NOP receptor; Neuroprotection; Nociceptin/orphanin FQ; Parkinson's disease; SB-612111; α-Synuclein