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Distinct effects of atypical 1,4‐dihydropyridines on 1‐methyl‐4‐phenylpyridinium‐induced toxicity
Author(s) -
Klimaviciusa Linda,
Klusa Vija,
Duburs Gunars,
Kaasik Allen,
Kalda Anti,
Zharkovsky Alexander
Publication year - 2006
Publication title -
cell biochemistry and function
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.933
H-Index - 61
eISSN - 1099-0844
pISSN - 0263-6484
DOI - 10.1002/cbf.1340
Subject(s) - chemistry , neuroprotection , oxidative stress , dihydropyridine , mechanism of action , programmed cell death , mitochondrion , pharmacology , biochemistry , calcium in biology , calcium , stereochemistry , intracellular , biology , in vitro , apoptosis , organic chemistry
Abstract Our previous data obtained from in vivo experiments demonstrated high neuroprotective effects of three novel atypical neuronal non‐calcium antagonistic 1,4‐dihydropyridine (DHP) derivatives cerebrocrast, glutapyrone and tauropyrone. The present studies were carried out in vitro to clarify, at least in part, their mechanism of action in primary culture of cerebellar granule cells by use of 1‐methyl‐4‐phenylpyridinium (MPP + ) as a neurotoxic agent which causes dramatic oxidative stress. Cerebrocrast (highly lipophilic, with a classical two‐ring structure) dose‐dependently (0.01–10.0 µM, EC 50 = 13 nM) reduced MPP + ‐induced cell death. At the same time, the calcium antagonist nimodipine (reference drug) protected cell death at much higher concentrations (EC 50 = 12.4 µM). Cerebrocrast decreased also the generation of reactive oxygen species and loss of mitochondrial membrane potential. In contrast, low lipophilic amino acid‐containing DHPs glutapyrone and tauropyrone (glutamate‐ and taurine‐containing, correspondingly) were without significant effects indicating their distinct mode of action in comparison to cerebrocrast. We have demonstrated for the first time an ability of atypical non‐calcium antagonistic DHP cerebrocrast (which has classical DHP structure elements and high lipophilicity) to protect MPP + ‐induced deterioration of mitochondrial bioenergetics. One may suggest mitochondria as an essential intracellular target for the neuroprotective action of cerebrocrast and indicate its usefulness in the treatment of Parkinson's disease. Copyright © 2006 John Wiley & Sons, Ltd.