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: Ludovico Arcuri, Riccardo Viaro, Simone Bido, Francesco Longo, Mariangela Calcagno, Pierre-Olivier Fernagut, Nurulain T Zaveri, Girolamo Calò, Erwan Bezard, Michele Morari
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 89 Pg. 55-64 (May 2016) ISSN: 1095-953X [Electronic] United States
• PMID: 26804029 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016. Published by Elsevier Inc.

Chemical References

• Cycloheptanes
• Narcotic Antagonists
• Piperidines
• Receptors, Opioid
• cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol
• Nociceptin Receptor

Topics

• Animals
• Cycloheptanes (administration & dosage)
• Dopaminergic Neurons (drug effects, metabolism, pathology)
• Gene Deletion
• Locomotion (drug effects)
• MPTP Poisoning
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Narcotic Antagonists (administration & dosage)
• Parkinsonian Disorders (genetics, metabolism, pathology)
• Piperidines (administration & dosage)
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid (genetics, metabolism)
• Substantia Nigra (drug effects, metabolism, pathology)
• Nociceptin Receptor