The 5-HT 2A/2C inverse agonist nelotanserin alleviates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset.

Autor: Kwan C; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, Quebec, Canada., Frouni I; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, Quebec, Canada.; Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, Quebec, Canada., Bédard D; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, Quebec, Canada., Hamadjida A; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, Quebec, Canada., Nuara SG; Comparative Medicine & Animal Resource Centre, McGill University, Montreal, Quebec, Canada., Gourdon JC; Comparative Medicine & Animal Resource Centre, McGill University, Montreal, Quebec, Canada., Huot P; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, Quebec, Canada.; Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, Quebec, Canada.; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.; Movement Disorder Clinic, Division of Neurology, Department of Neurosciences, McGill University Health Centre, Montreal, QC, Canada.
Jazyk: angličtina
Zdroj: The European journal of neuroscience [Eur J Neurosci] 2024 Mar; Vol. 59 (6), pp. 1169-1176. Date of Electronic Publication: 2023 Jul 28.
DOI: 10.1111/ejn.16104
Abstrakt: Nelotanserin is a serotonin 2A and 2C (5-HT 2A/2C ) inverse agonist that was previously tested in the clinic for rapid-eye movement sleep behaviour disorder and psychosis in patients with Parkinson's disease (PD) dementia. Its effect on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia has however not been investigated. As 5-HT 2A antagonism/inverse agonism is a validated approach to alleviate dyskinesia, we undertook the current study to evaluate the anti-dyskinetic potential of nelotanserin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Parkinsonism was induced in six common marmosets (Callithrix jacchus, three females and three males) that were then chronically treated with L-DOPA to induce dyskinesia. On experimental days, they were administered L-DOPA in combination with vehicle or nelotanserin (0.1, 0.3 and 1 mg/kg) subcutaneously, in a randomised fashion. Dyskinesia and parkinsonism were rated post hoc by a blinded observer. In comparison to vehicle, the addition of nelotanserin 0.3 and 1 mg/kg to L-DOPA diminished peak dose dyskinesia by 47% (P < 0.05) and 69% (P < 0.001). Nelotanserin 0.3 and 1 mg/kg also reduced the severity of global dyskinesia, by 40% (P < 0.01) and 55% (P < 0.001), when compared to vehicle. Nelotanserin 0.1 mg/kg did not alleviate peak dose or global dyskinesia severity. Nelotanserin had no impact on the anti-parkinsonian action of L-DOPA. Our results highlight that nelotanserin may represent an efficacious anti-dyskinetic drug and provide incremental evidence of the potential benefit of 5-HT 2A/2C antagonism/inverse agonism for drug-induced dyskinesia in PD.
(© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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