Objective: To determine the effect of the serotonin 2A/2C (5-HT_2A/2C) receptor inverse agonist nelotanserin on dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset.

Background: Nelotanserin is a potent 5-HT_2A inverse agonist and moderate 5-HT_2C inverse agonist. Nelotanserin has previously been investigated in the clinic for the treatment of dementia with Lewy bodies and Parkinson’s disease (PD) dementia, specifically visual hallucinations and rapid eye movement sleep behaviour disorder. However, the development of nelotanserin has since been discontinued, as it failed to meet its endpoints.

Notwithstanding its lack of anti-psychotic effect in the parkinsonian population in the clinic, the effect of nelotanserin on dyskinesia remains poorly characterised. As 5-HT_2A antagonism is a validated strategy to reduce dyskinesia, at least in experimental models of PD, we sought to assess the anti-dyskinetic action of nelotanserin in the parkinsonian primate and also evaluated the effect of nelotanserin on parkinsonism.

Method: Six MPTP-lesioned marmosets with stable dyskinesias were administered vehicle or nelotanserin (0.1, 0.3 and 1 mg/kg), sub-cutaneously, in combination with L-3,4-dihydroxyphenylalanine (L-DOPA)/benserazide (15/3.75 mg/kg), in a randomised fashion. Dyskinesia and parkinsonism were then scored by a blinded rater.

Results: Compared to L-DOPA/vehicle, nelotanserin 0.3 mg/kg diminished peak dose dyskinesia by 47% (P < 0.05), while nelotanserin 1 mg/kg reduced peak dose dyskinesia by 69% (P < 0.001). In comparison to L-DOPA/vehicle nelotanserin 0.3 mg/kg decreased global dyskinesia by 40% (P < 0.01), while the dose of 1 mg/kg conferred a 55% reduction (P < 0.001). Nelotanserin 0.1 mg/kg did not have any effect on peak dose or global dyskinesia severity. Nelotanserin, at any dose, did not modify the anti-parkinsonian action of L-DOPA.

Conclusion: These results provide incremental pre-clinical evidence that 5-HT_2A antagonism is an efficacious anti-dyskinetic approach.

« Back to 2023 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-the-5-ht2a-2c-inverse-agonist-nelotanserin-on-dyskinesia-in-the-mptp-lesioned-marmoset/