Alpha7 nicotinic receptor- mediated reduction of L-DOPA-induced dyskinesia in 6OHDA rat model of Parkinson’s Disease

Abstract

Introduction: In Parkinson’s Disease (PD) induction of involuntary movements (AIMs) or dyskinesia, after long-term L-DOPA therapy is a major problem. Evidence shows that nicotine can protect against nigrostriatal damage and reduce L-DOPA-induced dyskinesia, and studies in transgenic mice suggest that deletion of α7 nAChRs leads to increased L-DOPA-induced AIMs in animals with nigrostriatal lesion compared to lesioned wild-type littermates. Similarly, nicotinic agonists selective for the α7 nAChRs have been shown to reduce dyskinesia. The discovery of positive allosteric modulators (PAMs) such as PNU-120596 selective for nAChRs has extended the repertoire of therapeutic strategies for targeting various subtypes of nAChRs. PNU-120596 increases both agonist efficacy and open time of the α7 nAChRs channel, resulting in extended nicotinic stimulation. The aim of this study was to assess the role of α7 nAChRs selective PAMs in dyskinesia reduction using rat AIMS models, and to make direct comparison to nicotine. Methods: Rats unilaterally lesioned with 8 µg 6-hydroxydopamine were primed with oral L-DOPA (8 mg/kg) plus benserazide (15 mg/kg) once daily for 3 weeks until AIMs were fully developed. Approach for statistical analysis: AIMs experiments were analysed using a repeated measure two-way ANOVA followed by Dunnett’s post-hoc tests. *p≤ 0.05 was considered statistically significant, data are presented as mean ± SEM. Results and conclusions: Treatment with 0.01 or 0.03mg/kg nicotine reduced AIMS by 33%, whereas 0.3mg/kg nicotine (n=16; *p≤ 0.05) reduced AIMS by 34% (n=16; *p≤ 0.05). Treatment with 1mg/kg or 3mg/kg PNU-120596 reduced AIMS by 34% and 44% (n=16; *p≤ 0.05); respectively. Combined treatment with 0.01 or 0.03mg/kg nicotine and 1mg/kg PNU-120596 enhanced the anti-dyskinetic effects by 57% (n=12; *p≤ 0.05) compared to each drug alone, resulting in an additive effect. These findings provide an essential role for α7 nAChRs in the anti-dyskinetic effect of nicotine. Targeting α7 nAChRs which has a rapid desensitization kinetic using PAMs, presents advantages such as reduced toxicity, improved pharmacokinetics, and better selectivity for the receptor target.