title: The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease.
abstract: 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 Cav1.3L-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.
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: E
authors.initials: E
authors.lastname: Ilijic
authors.forename: J N
authors.initials: JN
authors.lastname: Guzman
authors.forename: D J
authors.initials: DJ
authors.lastname: Surmeier
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000097:blood / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000097:blood / Q000502:physiology*; D004095:Dihydropyridines / Q000494:pharmacology; D004195:Disease Models, Animal; D017275:Isradipine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000097:blood / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000097:blood / Q000188:drug therapy*
chemical_list: C485995:Cacna1d protein, mouse; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D018696:Neuroprotective Agents; D017275:Isradipine