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Inhibition of Excessive Neuronal Apoptosis by the Calcium Antagonist Amlodipine and Antioxidants in Cerebellar Granule Cells
Author(s) -
Mason R. Preston,
Leeds Peter R.,
Jacob Robert F.,
Hough Christopher J.,
Zhang KaiGao,
Mason Pamela E.,
Chuang DeMaw
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.721448.x
Subject(s) - pharmacology , channel blocker , chemistry , neuroprotection , nitric oxide , oxidative stress , voltage dependent calcium channel , apoptosis , calcium channel , intracellular , calcium , biochemistry , biology , organic chemistry
Neuronal cell death as a result of apoptosis is associated with cerebrovascular stroke and various neurodegenerative disorders. Pharmacological agents that maintain normal intracellular Ca 2+ levels and inhibit cellular oxidative stress may be effective in blocking abnormal neuronal apoptosis. In this study, a spontaneous (also referred to as age‐induced) model of apoptosis consisting of rat cerebellar granule cells was used to evaluate the antiapoptotic activities of voltage‐sensitive Ca 2+ channel blockers and various antioxidants. The results of these experiments demonstrated that the charged, dihydropyridine Ca 2+ channel blocker amlodipine had very potent neuroprotective activity in this system, compared with antioxidants and neutral Ca 2+ channel blockers (nifedipine and nimodipine). Within its effective pharmacological range (10‐100 n M ), amlodipine attenuated intracellular neuronal Ca 2+ increases elicited by KCl depolarization but did not affect Ca 2+ changes triggered by N ‐methyl‐D‐aspartate receptor activation. Amlodipine also inhibited free radical‐induced damage to lipid constituents of the membrane in a dose‐dependent manner, independent of Ca 2+ channel modulation. In parallel experiments, spontaneous neuronal apoptosis was inhibited in dose‐ and time‐dependent manners by antioxidants (U‐78439G, α‐tocopherol, and melatonin), nitric oxide synthase inhibitors ( N ‐nitro‐L‐arginine and N ‐nitro‐D‐arginine), and a nitric oxide chelator (hemoglobin) in the micromolar range. These results suggest that spontaneous neuronal apoptosis is associated with excessive Ca 2+ influx, leading to further intracellular Ca 2+ increases and the generation of reactive oxygen species. Agents such as amlodipine that block voltage‐sensitive Ca 2+ channels and inhibit cellular oxidative stress may be effective in the treatment of cerebrovascular stroke and neurodegenerative diseases associated with excessive apoptosis.