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Inhibition of Excessive Neuronal Apoptosis by the Calcium Antagonist Amlodipine and Antioxidants in Cerebellar Granule Cells.
- Source :
-
Journal of Neurochemistry . Apr99, Vol. 72 Issue 4, p1448-1456. 9p. 2 Black and White Photographs, 8 Graphs. - Publication Year :
- 1999
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Abstract
- Neuronal cell death as a result of apoptosis is associated with cerebrovascular stroke and various neurodegenerative disorders. Pharmacological agents that maintain normal intracellular Ca2+ 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 Ca2+ channel blockers and various antioxidants. The results of these experiments demonstrated that the charged, dihydropyridine Ca2+ channel blocker amlodipine had very potent neuroprotective activity in this system, compared with antioxidants and neutral Ca2+ channel blockers (nifedipine and nimodipine). Within its effective pharmacological range (10-100 nM), amlodipine attenuated intracellular neuronal Ca2+ increases elicited by KCl depolarization but did not affect Ca2+ 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 Ca2+ 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 Ca2+ influx, leading to further intracellular Ca2+ increases and the generation of reactive oxygen species. Agents such as amlodipine that block voltage-sensitive Ca2+ channels and inhibit cellular oxidative stress may be effective in the treatment of cerebrovascular stroke and neurodegenerative diseases associated with excessive apoptosis. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CALCIUM antagonists
*ANTIOXIDANTS
Subjects
Details
- Language :
- English
- ISSN :
- 00223042
- Volume :
- 72
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Journal of Neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 5635541
- Full Text :
- https://doi.org/10.1046/j.1471-4159.1999.721448.x