A behavioural evaluation of the potential of nNOS inhibitors to control dyskinesia in animal models of Parkinson’s disease

Abstract

Long-term dopaminergic therapy in Parkinson’s disease (PD) can lead to motor complications including dyskinesia which can be treated with amantadine, an N-methyl-D-aspartate (NMDA) receptor antagonist. NMDA receptor activation is linked with nitric oxide (NO) production and changes in synaptic plasticity, suggesting a role in dyskinesia. This led to the hypothesis that NO, produced by neuronal nitric oxide synthase (nNOS), contributes to the occurrence and evolution of dyskinesia in PD. Therefore, these studies investigated the effects of nNOS inhibition, using the nNOS inhibitors ARR17477 and 7-nitroindazole (7-NI), on the dyskinesia expression and priming processes in rodent and primate models of PD following L-dopa and dopamine agonist treatment.

To explore the role of nNOS inhibition on established dyskinesia, 6-OHDA-lesioned rats, primed to exhibit stable abnormal involuntary movements (AIMs), the rodent analogue of dyskinesia, were acutely challenged with nNOS inhibitors plus L-dopa or ropinirole. No reduction in AIMs was observed following nNOS inhibition.

In order to investigate the potential for nNOS inhibitors to reduce the priming for AIMs, naïve 6-OHDA-lesioned rats were treated chronically with ARR17477 or 7-NI plus either L-dopa or ropinirole. Again, there was no beneficial effect of nNOS inhibition on the emergence of L-dopa- or ropinirole-induced AIMs.

nNOS inhibition was also investigated in MPTP-treated primates, the gold standard behavioural model of PD. ARR17477 did not reduce the expression of established dyskinesia following L-dopa or ropinirole treatment. Similarly nNOS inhibition did not attenuate L-dopa-induced priming for dyskinesia in this model.

In conclusion, inhibition of nNOS in 6-OHDA-lesioned rats and MPTP-treated primates did not reduce the expression or priming of L-dopa- or ropinirole-induced dyskinesia. These findings do not support a role for nitric oxide in processes underlying dyskinesia and suggest that nNOS inhibitors would not be beneficial in either preventing or attenuating motor complications in PD patients.

Date of Award	1 Nov 2012
Original language	English
Awarding Institution	King's College London
Supervisor	Sarah Salvage (Supervisor) & Peter Jenner (Supervisor)