Bösel Julian, Gandor Florin, Harms Christoph, Synowitz Michael, Harms Ulrike, Djoufack Pierre Chryso, Megow Dirk, Dirnagl Ulrich, Hörtnagl Heide, Fink Klaus B, Endres Matthias
Klinik und Poliklinik für Neurologie, Charité- Universitätsmedizin Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany.
J Neurochem. 2005 Mar;92(6):1386-98. doi: 10.1111/j.1471-4159.2004.02980.x.
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.
他汀类药物[3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂]具有不依赖胆固醇的多效性作用，包括抗血栓形成、抗炎和抗氧化特性。在此，我们在体外不同细胞损伤模型中研究了阿托伐他汀对神经元的直接保护作用。原代皮质神经元先用阿托伐他汀预处理，然后暴露于（i）谷氨酸、（ii）氧糖剥夺或（iii）几种凋亡诱导化合物。碘化丙啶染色、核形态、乳酸脱氢酶释放和线粒体四氮唑代谢表明，阿托伐他汀可显著保护神经元免受谷氨酸诱导的兴奋性毒性，但对氧糖剥夺或凋亡性细胞死亡无保护作用。这种抗兴奋性毒性作用在预处理2-4天时明显，但每日给药或短期预处理则无此作用。其保护特性的产生与3-羟基-3-甲基戊二酰辅酶A还原酶抑制无关，因为与甲羟戊酸或其他类异戊二烯共同处理不会逆转或减弱神经保护作用。阿托伐他汀减弱了谷氨酸诱导的细胞内钙增加，这与N-甲基-D-天冬氨酸（NMDA）受体功能的调节有关。综上所述，阿托伐他汀发挥了独立于3-羟基-3-甲基戊二酰辅酶A还原酶抑制的特异性抗兴奋性毒性作用，具有潜在的治疗意义。
