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

Ema Ilijic, Jaime N Guzman-Lucero, Dalton James Surmeier Jr*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

138 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)364-371
Number of pages8
JournalNeurobiology of Disease
Volume43
Issue number2
DOIs
StatePublished - Aug 1 2011

Keywords

  • 6-OHDA
  • Isradipine
  • Neuroprotection
  • Substantia nigra

ASJC Scopus subject areas

  • Neurology

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