Evaluation of nicotine and its analogues to remediate dyskinesias and cognitive deficits associated with Parkinson's disease

Extensive epidemiologic studies indicate that tobacco use is inversely related to
the incidence of Parkinson’s disease (PD). Evidence shows nicotine can protect
against nigrostriatal damage and can also reduce L-DOPA-induced dyskinesia. We propose to investigate the underlying mechanisms by which compounds modulating the alpha7 or the alpha4beta2 nicotinic acetylcholine receptors (nAChRs) can alleviate the symptoms of PD and thus exert potential therapeutic effects of (a) suppressing the abnormal involuntary movements and also (b) restoring impaired executive function and working memory within a rodent model of PD. To provide a more clinically-relevant model of PD-associated impaired function, the models will be examined following L-DOPA treatment as this is the commonly prescribed medication for PD. Depending on the outcome, evaluation of a series of nicotinic compounds selective for alpha4beta2 and/or alpha7 subtype will be evaluated in L-DOPAprimed, unilaterally 6-hydroxydopamine lesioned rats in both models to unravel the underlying mechanisms behind the restoration of motor and cognitive function. Tests will also include positive allosteric modulators at the respective nAChR subtypes. Finally, confirmation of selectivity and the regional sites of action will be established using site-directed injections of selective nAChR receptor antagonists, methyllycaconitine or dihydro-beta-erythroidine.
Based on preliminary data, it is anticipated that alpha7 PAMs may provide a clinically effective treatment in managing the cognitive symptoms that may overcome the side effects associated with conventional treatment of PD.