Objective/Rationale:
The idea that compounds targeting neuronal nicotinic receptors may be useful for the treatment of L-dopa-induced abnormal involuntary movements (AIMs), or dyskinesias, stemmed from preclinical studies showing that nicotine reduces L-dopa-induced AIMs by ~50%. The preferential presence of certain nicotinic receptor subtypes in the brain raises the possibility that, unlike nicotine, drugs selectively targeting one or more of these neuronal nicotinic subtypes may provide optimal therapeutic benefit for treatment of L-dopa-induced dyskinesias in PD, with a minimum of side effects.
Project Description:
This proposal is designed to extend the findings with nicotine by assessing a series of agonists with varying pharmacological properties in order to identify the nicotinic receptor subtype agonists that best reduce L-dopa-induced AIMs without worsening parkinsonism. Novel chemical compounds with varying activity at different targeted neuronal nicotinic receptor subtype configurations will be studied in a well-established relatively inexpensive rodent model of PD, the 6-OHDA-lesioned rat. The drug will be tested for several weeks to ensure efficacy is maintained. Parkinsonism will be assessed to ensure the drugs do not worsen motor function. Plasma drug levels will be monitored to document exposure and to evaluate potential pharmacokinetic/pharmacodynamic relationships. L-dopa levels will also be monitored to ensure that test compounds do not affect L-dopa metabolism.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The primary therapy for PD is treatment with L-dopa to improve motor symptoms occurring with dopaminergic loss. However, L-dopa becomes less effective with continued disease progression and it leads to disabling complications, including AIMs or dyskinesias that can be as debilitating as PD itself. Current drug treatments for dyskinesias are limited, thus raising a critical need for alternate therapies. Findings from this study offer the possibility of selectively targeting optimal therapeutic pharmacology with diminished adverse effects.
Anticipated Outcome:
The primary nicotinic receptor subtypes in the striatum are the ?4?2* and ?6?2* subunits, as well as a smaller population of ?7 nAChRs. The objective of this proposal is to utilize Targacept’s expertise in selective nicotinic ligand design to identify the optimal nicotinic pharmacology involved in reduction of L-dopa-induced AIMs without worsening parkinsonism. Ultimately, the knowledge gained from this research will help design safe, effective drugs toward that end.
Final Outcome
Results from these studies show that some but not all compounds with selectivity for specific nicotinic receptors in the brain decreased the number of “abnormal involuntary movements” (AIMs, or dyskinesias) induced by the Parkinson’s disease drug levodopa in pre-clinical models rendered parkinsonian by a chemical lesion, without worsening motor symptoms. Specifically, a reduction in levodopa-induced AIMs was associated with a compound’s ability to inhibit neuronal activity at nicotinic receptors containing beta2 subunits (in combination with alpha4 and/or alpha6 subunits). Additionally, we found that there appears to be some variability in the therapeutic effects of the nicotinic compounds tested depending on the severity of dyskinesia symptoms, where less impaired pre-clinical models were more responsive to treatment. Analyses of the effects of the nicotinic compounds in the pre-clinical model show that the most pronounced effects are on treatment of AIMs in facial muscle groups, followed by those presenting in limb and trunk muscle groups. Overall, these data support the idea that compounds demonstrating functional inhibition properties at beta2-containing nicotinic receptors in the brain represent good candidates for development as levodopa-induced dyskinesia therapies. One compound showing efficacy in the pre-clinical studies described above is currently undergoing additional testing in another pre-clinical model.