Pre-clinical Models Specifying Nicotinic Receptor Targets in Parkinson's Disease Neuroprotection
Target Validation, 2011
The scientific community has known since 1959 that tobacco use has apparent protective effects against Parkinson’s disease (PD), and some animal models suggest that this protective effect arises from nicotine itself. Nicotine therefore represents a candidate “lead” neuroprotective drug for those diagnosed with early-stage PD. However, nicotine is a suboptimal therapeutic drug because of (a) its poor selectivity among nicotine receptors, (b) its rapid metabolism, and (c) the tremendous political and ideological objections that still apply to nicotine patches. To test better derivatives of nicotine, we need a pre-clinical model for the neuroprotective effects of nicotine-like drugs.
We will give steady doses of nicotine to a special strain of models, which provide a model for some aspects of the neurodegeneration in Parkinson’s disease. The steady doses will be delivered for several months by a special implanted minipump in order to mimic the nicotine provided by smoking, by smokeless tobacco use, or by a nicotine patch. We will test the mice with behavioral assays for both the motor and non-motor aspects of PD. We will also perform microscopic assays to assess neurodegeneration directly. We will characterize any changes produced by nicotine in the rate of neurodegeneration.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The Michael J. Fox Foundation is supporting a clinical trial to treat early-stage PD patients with nicotine patches. The clinical trial might yield a decision on the safety of the nicotine patch for PD patients, and / or a clearly positive therapeutic result. It will still be important to develop an optimal, selective, nicotine derivative for PD neuroprotection. If the clinical trial produces a negative result, the target data produced by this project will enable assays for more relevant nicotine-like drugs. Thus, however the ongoing trial ends, this proposed project will have interest for PD therapeutics.
The work will tell us whether the thy1-alpha synuclein models provide a good model for the neuroprotective effects of nicotine. If so, further research can employ this model to test which specific nicotine receptors are involved, and which drugs best act via these receptors to protect neurons. If a good neuroprotective drug can be found, it can be given to patients with early-stage PD.
Bren Professor of Biology at California Institute of Technology
Location: Pasadena, California, United States