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. 2011 Aug;43(2):364-71.
doi: 10.1016/j.nbd.2011.04.007. Epub 2011 Apr 16.

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

E Ilijic  1 , J N Guzman, D J Surmeier
Affiliations

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

E Ilijic et al. Neurobiol Dis. 2011 Aug.

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.

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Figures

Fig 1
Fig 1
Near complete lesion and partial nigrostriatal lesion induced with different 6-OHDA doses. (A) Unilateral intrastriatal injection of 3.5 μg 6-OHDA caused a near complete elimination of TH-immunoreactive fibers throughout the rostro-caudal axis of lateral striatum (A) and a near complete loss of SNc DA cells (B). SNc is shown in coronal sections at different levels of mouse midbrain in rostro-caudal order. (C) Fluorescence microphotographs of TH positive neurons counterstained with ethidium bromide in coronal sections through the midbrain of mice injected with 2.5 μg 6-OHDA. On the side contralateral to the lesion (intact side) the SNc contained a normal number of large neurons with dendrites positive for TH fluorescence. Ethidium bromide counterstaining overlaped with TH positive neurons. Ipsilateral to the injection site (lesion side) there were few viable neurons labeled with TH and ethidium bromide fluorescence. Ctx - cortex, CPu-caudate putamen (striatum), GP-globus pallidus, VTA-ventral tegmental area, SNc – substantia nigra pars compacta, SNr - substantia nigra pars reticulata, TH – tyrosine hydroxylase, Et-Br - ethidium bromide.
Fig 2
Fig 2
Isradipine pre-treatment reduced 6-OHDA induced neurotoxicity at the striatal level. Representative microphotographs showing TH immunoreactive fibers in the striatum after unilateral 6-OHDA injection in mice pretreated with (A) vehicle, and with (B) isradipine (plasma concentration 10.4 ng/ml). Approximately equally spaced, five coronal sections of the left striatum are shown. Protection afforded by isradipine was evident in all rostro-caudal levels. (C) The curve shows a nonlinear regression of relative TH+ striatal fiber density and isradipine plasma concentration with a Hill coefficient of 3 and an IC50=7.2 ng/ml. Starting point of the curve is at the median of TH positive fibers in the vehicle group (median=9.7, n=7). (D) Protective effect of isradipine at the striatal level was dose-dependent as shown from 6 mice. (E) Box-plots summarizing the relative percent TH+ fiber density in the vehicle (n=8), and isradipine pretreated group (n=7). Isradipine significantly reduced toxic effect of 6-OHDA in the striatum. Statistical significance in all plots is shown by asterisks and determined using non-parametric test (Kruskal-Wallis ANOVA). Probability (P) threshold for statistical significance was 0.05. Cpu – caudate-putamen, GP-globus pallidus, Acb – nucleus accumbens
Fig 3
Fig 3
Isradipine pre-treatment increased the number of surviving SNc DA cells after 6-OHDA induced degeneration. (A) Microphotographs of coronal sections through the ventral mesencephalon showing TH positive cells on the intact side, 6-OHDA injected group (column “6-OHDA+ vehicle”), and 6-OHDA injected group pretreated with isradipine (column “6-OHDA + isradipine”). Sections show four different levels of the SNc. Note increased number of TH positive cells in isradipine pretreated group (plasma concentration 10.4 ng/ml). (B) The curve shows a nonlinear regression of relative TH+ cells and isradipine plasma concentration with a Hill coefficient of 3 and an IC50=5.0 ng/ml. (C) Protective effect of isradipine at the nigral level was dose-dependent as shown from 6 mice. (D) Box-plots summarizing the relative percent TH positive cells in the vehicle (n=8), and isradipine pretreated group (n=7). Isradipine significantly reduced toxic effect of 6-OHDA at the level of DA cell bodies. Statistical significance in all plots is shown by asterisks and determined using non-parametric test (Mann-Whitney test). Probability (P) threshold for statistical significance was 0.05. (E) Box-plots summarizing the relative percent of TH positive cells in the ventral tegemental area (VTA) after striatal 6-OHDA injection in both vehicle and isradipine pretreated animals (no significant difference is found). (F) Plot of the fraction of L-type calcium channels as a function of isradipine concentration (red line) and of lower affinity antagonist nifedipine (green line) at −60mV. Roughly 60% of Cav1.3 channels are antagonized by ~3 ng/ml of isradipine (~8 nM) which is the threshold for protection against 6-OHDA. Almost complete protection of cell bodies is achieved by 50 ng/ml (~135 nM) of isradipine that antagonizes 95% or more of channels.
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