Objective/Rationale:
Parkinson’s disease is associated with changes in the electrical activity of nerve cells in the basal ganglia and thalamus, including the emergence of abnormal burst discharges, due in part to dysfunction of a specific type of ion channel on nerve cell membranes, called T-type calcium channel. We hypothesize that abnormal bursting contributes to the development of parkinsonian motor signs, and that blockade of T-type calcium channels may lessen the incidence of bursts, and ameliorate parkinsonism.
Project Description:
We will examine the antiparkinsonian effects of highly selective T-type calcium channel inhibitors in a pre-clinical model of Parkinson’s disease. These drugs were recently developed by our colleagues at Vanderbilt University. We will first study whether the drugs enter the brain of the models. These experiments will be followed by behavioral studies of the effects of the drugs, and a comparison with the effects of the gold-standard antiparkinsonian medication, levodopa. Finally, we plan to examine the effects and side effects of chronic daily treatment with the new compounds, and assess the effects of combining them with levodopa treatment.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If the T-type calcium channel inhibitors are found to be effective and safe antiparkinsonian agents in the pre-clinical model of Parkinson’s disease, clinical trial studies can be carried out to examine proper dosing, safety and antiparkinsonian efficacy of these drugs in humans. If successful, the studies may lead to the development of new non-dopaminergic alternative (or add-on) medications in parkinsonian patients, especially for those who no longer tolerate high-dose levodopa therapy.
Anticipated Outcome:
The proposed work will allow us to learn if newly developed highly selective T-type calcium channels are possible drug targets for helping patients with Parkinson’s disease. If so, the studies will lead to early phase clinical trials in humans. A positive outcome of our studies would also lead to increased efforts of the drug development team at Vanderbilt University to create more specific and potent drugs targeting these channels for future use in humans.
Final Outcome
This study examined potential antiparkinsonian effects of selective T-type calcium channel inhibitors -- a novel group of compounds -- in pre-clinical models with Parkinson's disease (PD) features. We first demonstrated that novel T-type calcium channel inhibitors enter the brain and stay there for at least 24 hours at measurable levels. We then treated the models with the compounds and observed their behavior. We concluded that the compounds likely have a therapeutic effect, although not as strong as that of levodopa, the most widely prescribed drug for Parkinson's. Although T-type calcium channel inhibitors may affect heartbeat, we did not find any undesirable side effects other than mild slowing of the heart in our models treated with high doses of one of the compounds. We did, however, find that ML218, the most extensively studied compound, had significantly affected sleep and digestion. We combined low-dose ML218 with low-dose levodopa but did not find this combination more potent than levodopa or ML218 alone. Overall, these studies showed that ML218 has a modest therapeutic effect, but noticeable side effects limit the use of this compound. Adding ML218 to levodopa does not have an additional therapeutic benefit.
October 2014