Amelioration of Mitochondrial Oxidant Stress by Isradipine and Rasagiline

Study Rationale:                   
The cardinal motor symptoms of Parkinson’s disease (PD) are caused by the degeneration of dopaminergic neurons. One potential cause of this degeneration is calcium entry into dopamine neurons through L-type channels. Isradipine, an FDA-approved antagonist for these channels, is now being tested in a Phase III clinical trial for its ability to slow PD progression. Another potential cause of degeneration is mitochondrial oxidant stress created by monoamine oxidase metabolism of dopamine. This study will explore this potential cause in the hope that pharmacological antagonism of this pathway with rasagiline, in combination with antagonism of calcium channels by isradipine, will prove to be an effective neuroprotective therapy in PD. This conclusion is consistent with data from the Phase II clinical trial with isradipine in which a subset of the patients were taking rasagiline.

Hypothesis:
Monoamine oxidase-dependent dopamine metabolism increases mitochondrial oxidant stress, adding to the stress created by calcium entry through L-type channels.

Study Design:
The studies proposed take advantage of a variety of cutting-edge tools to gain a better understanding of the mechanisms driving degeneration in PD. First, the study will take advantage of new optical probes that can be delivered to key parts of dopaminergic neurons, allowing us to monitor how these regions are faring during activity and following drug treatment. Second, genetic strategies will be used to move monoamine oxidase away from mitochondria to determine whether their positioning is what allows them to create stress. Third, the interaction between rasagiline (an FDA-approved inhibitor of monoamine oxidase) and isradipine will be examined to determine if they can effectively work together to lower mitochondrial stress and slow disease progression. These powerful new tools will be used in pre-clinical and human models (dopamine neurons derived from induced pluripotent stem cells) to maximize their relevance to PD patients.

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
If the hypotheses to be tested are confirmed, the proposed studies would establish a compelling rationale for a Phase III clinical trial with the combination of rasagiline and isradipine.

Next Steps for Development:
For a Phase III trial to go forward, dose formulation and pharmacokinetics would have to be determined.