The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease

The motor symptoms of Parkinson's disease (PD) are due to the progressive loss of dopamine (DA) neurons in substantia nigra pars compacta (SNc). Nothing is known to slow the progression of the disease, making the identification of potential neuroprotective agents of great clinical importance. Previous studies using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have shown that antagonism of L-type Ca2+ channels protects SNc DA neurons. However, this was not true in a 6-hydroxydopamine (6-OHDA) model. One potential explanation for this discrepancy is that protection in the 6-OHDA model requires greater antagonism of Cav1.3 L-type Ca2+ channels thought to underlie vulnerability and this was not achievable with the low affinity dihydropyridine (DHP) antagonist used. To test this hypothesis, the DHP with the highest affinity for Cav1.3 L-type channels—isradipine—was systemically administered and then the DA toxin 6-OHDA injected intrastriatally. Twenty-five days later, neuroprotection and plasma concentration of isradipine were determined. This analysis revealed that isradipine produced a dose-dependent sparing of DA fibers and cell bodies at concentrations achievable in humans, suggesting that isradipine is a potentially viable neuroprotective agent for PD.

Research highlights
► Using a progressive model of Parkinson's disease created by intrastriatal 6-hydroxydopamine, the neuroprotective potential of the L-type Ca2+ channel antagonist isradipine was tested.
► Isradipine is dihydropyridine approved for human use in the treatment of hypertension.
► Systemic administration of isradipine protected both striatal dopaminergic terminals and parent cell bodies.
► Protection was dose-dependent and afforded by plasma concentrations of isradipine achievable in humans within FDA guidelines.