Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson’s disease.

Ludovico Arcuri, Riccardo Viaro, Simone Bido, Francesco Longo, Mariangela Calcagno, Pierre-Olivier Fernagut, Nurulain T. Zaveri, Girolamo Calò, Erwan Bezard, Michele Morari
Neurobiology of Disease. 2016-05-01; 89: 55-64
DOI: 10.1016/j.nbd.2016.01.016

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1. Neurobiol Dis. 2016 May;89:55-64. doi: 10.1016/j.nbd.2016.01.016. Epub 2016 Jan
22.

Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ
contributes to dopamine cell loss in Parkinson’s disease.

Arcuri L(1), Viaro R(2), Bido S(1), Longo F(1), Calcagno M(1), Fernagut PO(3),
Zaveri NT(4), Calò G(1), Bezard E(3), Morari M(5).

Author information:
(1)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.
(2)Department of Biomedical and Specialty Surgical Sciences, Section of Human
Physiology, University of Ferrara, via Fossato di Mortara 19, 44121 Ferrara,
Italy.
(3)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR
5293, F-33000 Bordeaux, France.
(4)Astraea Therapeutics, 320 Logue Avenue, Mountain View, CA 94040, USA.
(5)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: .

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-tetrahy
dro-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.

Copyright © 2016. Published by Elsevier Inc.

DOI: 10.1016/j.nbd.2016.01.016
PMCID: PMC5567676
PMID: 26804029 [Indexed for MEDLINE]

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