Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson's disease.
Identifieur interne : 000275 ( Main/Curation ); 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
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pubmed:26804029Le document en format XML
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<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>
</record>
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