Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson's disease.
Identifieur interne : 000275 ( Main/Exploration ); précédent : 000274; suivant : 000276Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson's disease.
Auteurs : Ludovico Arcuri [Italie] ; Riccardo Viaro [Italie] ; Simone Bido [Italie] ; Francesco Longo [Italie] ; Mariangela Calcagno [Italie] ; Pierre-Olivier Fernagut [France] ; Nurulain T. Zaveri [États-Unis] ; Girolamo Cal [Italie] ; Erwan Bezard [France] ; Michele Morari [Italie]Source :
- Neurobiology of disease [ 1095-953X ] ; 2016.
English descriptors
- KwdEn :
- Animals, Cycloheptanes (administration & dosage), Dopaminergic Neurons (drug effects), Dopaminergic Neurons (metabolism), Dopaminergic Neurons (pathology), Gene Deletion, Locomotion (drug effects), MPTP Poisoning, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Narcotic Antagonists (administration & dosage), Parkinsonian Disorders (genetics), Parkinsonian Disorders (metabolism), Parkinsonian Disorders (pathology), Piperidines (administration & dosage), Rats, Rats, Sprague-Dawley, Receptors, Opioid (genetics), Receptors, Opioid (metabolism), Substantia Nigra (drug effects), Substantia Nigra (metabolism), Substantia Nigra (pathology).
- MESH :
- chemical , administration & dosage : Cycloheptanes, Narcotic Antagonists, Piperidines.
- drug effects : Dopaminergic Neurons, Locomotion, Substantia Nigra.
- genetics : Parkinsonian Disorders, Receptors, Opioid.
- metabolism : Dopaminergic Neurons, Parkinsonian Disorders, Receptors, Opioid, Substantia Nigra.
- pathology : Dopaminergic Neurons, Parkinsonian Disorders, Substantia Nigra.
- Animals, Gene Deletion, MPTP Poisoning, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Rats, Rats, Sprague-Dawley.
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.
Url:
DOI: 10.1016/j.nbd.2016.01.016
PubMed: 26804029
Affiliations:
- France, Italie, États-Unis
- Aquitaine, Californie, Nouvelle-Aquitaine
- Bordeaux
- Université de Bordeaux
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CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux</wicri:regionArea><placeName><region type="region" nuts="2">Nouvelle-Aquitaine</region><region type="old region" nuts="2">Aquitaine</region><settlement type="city">Bordeaux</settlement></placeName><orgName type="university">Université de Bordeaux</orgName></affiliation></author><author><name sortKey="Zaveri, Nurulain T" sort="Zaveri, Nurulain T" uniqKey="Zaveri N" first="Nurulain T" last="Zaveri">Nurulain T. 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Neuroscience Center and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>44121 Ferrara</wicri:noRegion></affiliation></author><author><name sortKey="Viaro, Riccardo" sort="Viaro, Riccardo" uniqKey="Viaro R" first="Riccardo" last="Viaro">Riccardo Viaro</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedical and Specialty Surgical Sciences, Section of Human Physiology, University of Ferrara, via Fossato di Mortara 19, 44121 Ferrara, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Biomedical and Specialty Surgical Sciences, Section of Human Physiology, University of Ferrara, via Fossato di Mortara 19, 44121 Ferrara</wicri:regionArea><wicri:noRegion>44121 Ferrara</wicri:noRegion></affiliation></author><author><name sortKey="Bido, Simone" sort="Bido, Simone" uniqKey="Bido S" first="Simone" last="Bido">Simone Bido</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>44121 Ferrara</wicri:noRegion></affiliation></author><author><name sortKey="Longo, Francesco" sort="Longo, Francesco" uniqKey="Longo F" first="Francesco" last="Longo">Francesco Longo</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>44121 Ferrara</wicri:noRegion></affiliation></author><author><name sortKey="Calcagno, Mariangela" sort="Calcagno, Mariangela" uniqKey="Calcagno M" first="Mariangela" last="Calcagno">Mariangela Calcagno</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>44121 Ferrara</wicri:noRegion></affiliation></author><author><name sortKey="Fernagut, Pierre Olivier" sort="Fernagut, Pierre Olivier" uniqKey="Fernagut P" first="Pierre-Olivier" last="Fernagut">Pierre-Olivier Fernagut</name><affiliation wicri:level="4"><nlm: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.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux</wicri:regionArea><placeName><region type="region" nuts="2">Nouvelle-Aquitaine</region><region type="old region" nuts="2">Aquitaine</region><settlement type="city">Bordeaux</settlement></placeName><orgName type="university">Université de Bordeaux</orgName></affiliation></author><author><name sortKey="Zaveri, Nurulain T" sort="Zaveri, Nurulain T" uniqKey="Zaveri N" first="Nurulain T" last="Zaveri">Nurulain T. Zaveri</name><affiliation wicri:level="2"><nlm:affiliation>Astraea Therapeutics, 320 Logue Avenue, Mountain View, CA 94040, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Astraea Therapeutics, 320 Logue Avenue, Mountain View, CA 94040</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Cal, Girolamo" sort="Cal, Girolamo" uniqKey="Cal G" first="Girolamo" last="Cal">Girolamo Cal</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>44121 Ferrara</wicri:noRegion></affiliation></author><author><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><affiliation wicri:level="4"><nlm: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.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux</wicri:regionArea><placeName><region type="region" nuts="2">Nouvelle-Aquitaine</region><region type="old region" nuts="2">Aquitaine</region><settlement type="city">Bordeaux</settlement></placeName><orgName type="university">Université de Bordeaux</orgName></affiliation></author><author><name sortKey="Morari, Michele" sort="Morari, Michele" uniqKey="Morari M" first="Michele" last="Morari">Michele Morari</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>44121 Ferrara</wicri:noRegion></affiliation></author></analytic><series><title level="j">Neurobiology of disease</title><idno type="eISSN">1095-953X</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Cycloheptanes (administration & dosage)</term><term>Dopaminergic Neurons (drug effects)</term><term>Dopaminergic Neurons (metabolism)</term><term>Dopaminergic Neurons (pathology)</term><term>Gene Deletion</term><term>Locomotion (drug effects)</term><term>MPTP Poisoning</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term><term>Narcotic Antagonists (administration & dosage)</term><term>Parkinsonian Disorders (genetics)</term><term>Parkinsonian Disorders (metabolism)</term><term>Parkinsonian Disorders (pathology)</term><term>Piperidines (administration & dosage)</term><term>Rats</term><term>Rats, Sprague-Dawley</term><term>Receptors, Opioid (genetics)</term><term>Receptors, Opioid (metabolism)</term><term>Substantia Nigra (drug effects)</term><term>Substantia Nigra (metabolism)</term><term>Substantia Nigra (pathology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Cycloheptanes</term><term>Narcotic Antagonists</term><term>Piperidines</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Dopaminergic Neurons</term><term>Locomotion</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Parkinsonian Disorders</term><term>Receptors, Opioid</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Dopaminergic Neurons</term><term>Parkinsonian Disorders</term><term>Receptors, Opioid</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Dopaminergic Neurons</term><term>Parkinsonian Disorders</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Gene Deletion</term><term>MPTP Poisoning</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term><term>Rats</term><term>Rats, Sprague-Dawley</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>France</li><li>Italie</li><li>États-Unis</li></country><region><li>Aquitaine</li><li>Californie</li><li>Nouvelle-Aquitaine</li></region><settlement><li>Bordeaux</li></settlement><orgName><li>Université de Bordeaux</li></orgName></list><tree><country name="Italie"><noRegion><name sortKey="Arcuri, Ludovico" sort="Arcuri, Ludovico" uniqKey="Arcuri L" first="Ludovico" last="Arcuri">Ludovico Arcuri</name></noRegion><name sortKey="Bido, Simone" sort="Bido, Simone" uniqKey="Bido S" first="Simone" last="Bido">Simone Bido</name><name sortKey="Cal, Girolamo" sort="Cal, Girolamo" uniqKey="Cal G" first="Girolamo" last="Cal">Girolamo Cal</name><name sortKey="Calcagno, Mariangela" sort="Calcagno, Mariangela" uniqKey="Calcagno M" first="Mariangela" last="Calcagno">Mariangela Calcagno</name><name sortKey="Longo, Francesco" sort="Longo, Francesco" uniqKey="Longo F" first="Francesco" last="Longo">Francesco Longo</name><name sortKey="Morari, Michele" sort="Morari, Michele" uniqKey="Morari M" first="Michele" last="Morari">Michele Morari</name><name sortKey="Viaro, Riccardo" sort="Viaro, Riccardo" uniqKey="Viaro R" first="Riccardo" last="Viaro">Riccardo Viaro</name></country><country name="France"><region name="Nouvelle-Aquitaine"><name sortKey="Fernagut, Pierre Olivier" sort="Fernagut, Pierre Olivier" uniqKey="Fernagut P" first="Pierre-Olivier" last="Fernagut">Pierre-Olivier Fernagut</name></region><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name></country><country name="États-Unis"><region name="Californie"><name sortKey="Zaveri, Nurulain T" sort="Zaveri, Nurulain T" uniqKey="Zaveri N" first="Nurulain T" last="Zaveri">Nurulain T. 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