Recent work by our group has shown that blocking L-type Ca2+ channels protects vulnerable dopaminergic neurons in three animal models Parkinson’s disease (PD). Isradipine, a high-blood-pressure drug, is used to block these channels and is approved for human use, but in a dose range lower than the one used in our animal experiments. The objective of our study is to determine whether systemic administration of this drug within a range approved for chronic human use is neuroprotective in an animal model of PD.
Our project has two components. Both components rely upon subcutaneous administration of the drug used in our earlier studies with timed-release pellets to mice. First, we will determine whether low doses of isradipine induce the change in the physiology of dopaminergic neurons that we think is responsible for neuroprotection. These studies will utilize electrophysiological methods in tissue slices from treated mice. Second, we will determine whether low doses of isradipine protect dopaminergic neurons from intrastriatal injection of a dopamine cell toxin – 6-hydroxydopamine. These studies will utilize quantitative, stereological methods to count surviving dopamine neurons in isradipine treated and placebo treated mice.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Currently, there is no proven neuroprotective treatment for PD. Our studies will provide a guide for translating our preclinical work into clinical trials to determine whether isradipine is neuroprotective in human PD patients. The development of a successful, well tolerated neuroprotective drug would be a major advance for the PD community.
Our experiments should provide us with a clear picture of the dose range in which isradipine protects dopaminergic neurons in animal models of PD. This information is critical to the design of human neuroprotection trials and the minimization of side-effects of isradipine in these trials.
Dr. Surmeier generated data on the pharmacokinetics of isradipine that was used to help determine potential efficacious doses of isradipine. The results of this study informed the design of the MJFF-funded STEADY-PD clinical study which is testing israpdine in PD patients. Additionally, Dr. Surmeier is working to identify additional calcium channel blockers through another MJFF-funded project.