Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones

被引:175
作者
Bösel, J
Gandor, F
Harms, C
Synowitz, M
Harms, U
Djoufack, PC
Megow, D
Dirnagl, U
Hörtnagl, H
Fink, KB
Endres, M
机构
[1] Univ Med Berlin Charite, Neurol Klin & Poliklin, D-10117 Berlin, Germany
[2] Max Delbruck Ctr Mol Med, Berlin, Germany
[3] Charite Univ Med Berlin, Inst Pharmakol & Toxikol, Berlin, Germany
[4] Univ Klinikum Bonn, Inst Pharmakol & Toxikol, Bonn, Germany
关键词
excitotoxicity; 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors; neuroprotection; statins;
D O I
10.1111/j.1471-4159.2004.02980.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Statins [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors] exert cholesterol-independent pleiotropic effects that include anti-thrombotic, anti-inflammatory, and anti-oxidative properties. Here, we examined direct protective effects of atorvastatin on neurones in different cell damage models in vitro. Primary cortical neurones were pre-treated with atorvastatin and then exposed to (i) glutamate, (ii) oxygen-glucose deprivation or (iii) several apoptosis-inducing compounds. Atorvastatin significantly protected from glutamate-induced excitotoxicity as evidenced by propidium iodide staining, nuclear morphology, release of lactate dehydrogenase, and mitochondrial tetrazolium metabolism, but not from oxygen-glucose deprivation or apoptotic cell death. This anti-excitototoxic effect was evident with 2-4 days pre-treatment but not with daily administration or shorter-term pre-treatment. The protective properties occurred independently of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition because co-treatment with mevalonate or other isoprenoids did not reverse or attenuate neuroprotection. Atorvastatin attenuated the glutamate-induced increase of intracellular calcium, which was associated with a modulation of NMDA receptor function. Taken together, atorvastatin exerts specific anti-excitotoxic effects independent of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition, which has potential therapeutic implications.
引用
收藏
页码:1386 / 1398
页数:13
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