Jantas D, Pytel M, Mozrzymas J W, Leskiewicz M, Regulska M, Antkiewicz-Michaluk L, Lason W
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
Neurochem Int. 2008 Mar-Apr;52(4-5):864-77. doi: 10.1016/j.neuint.2007.10.003. Epub 2007 Oct 6.
Memantine, a clinically used N-methyl-D-aspartate (NMDA)-receptor antagonist, has been shown to prevent apoptotic neuronal damage connected with the over-activity of NMDA receptors. In the present study, we examined the effect of memantine on staurosporine-, salsolinol- and doxorubicin-induced apoptosis in the SH-SY5Y cell line which does not possess functional NMDA receptors. Electrophysiological recordings and toxicity studies showed no response to NMDA-evoked currents in this cell line, irrespective of the stage of its neuronal differentiation. Memantine (0.1-2 microM) attenuated staurosporine-induced apoptosis as evidenced by reversal of the changes in mitochondrial membrane potential (DeltaPsi(m)) and decreased caspase-3 activity, lactate dehydrogenase (LDH) release and DNA fragmentation. Wortmannin (10 nM) and LY 294002 (10 microM) (inhibitors of phosphatidylinositol-3-kinase, PI3-K) reversed the inhibitory effect of memantine on the staurosporine-induced LDH release, suggesting that the PI3-K/Akt prosurvival pathway is a possible target for antiapoptotic action of memantine. Memantine at low micromolar concentrations also attenuated salsolinol- and doxorubicin-induced LDH release and DNA fragmentation, but only in the case of salsolinol was this effect accompanied by a decrease in caspase-3 activity. The present data indicate that memantine attenuates the toxic effects of various proapoptotic agents and the cytoprotective effect of memantine does not seem to be connected with its action on NMDA receptor but rather with its influence on intracellular pathways engaged in cellular survival/apoptotic processes.
美金刚是一种临床使用的N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，已被证明可预防与NMDA受体过度激活相关的凋亡性神经元损伤。在本研究中，我们检测了美金刚对丝裂霉素、salsolinol和阿霉素诱导的SH-SY5Y细胞系凋亡的影响，该细胞系不具有功能性NMDA受体。电生理记录和毒性研究表明，无论其神经元分化阶段如何，该细胞系对NMDA诱发的电流均无反应。美金刚（0.1 - 2 microM）可减轻丝裂霉素诱导的凋亡，线粒体膜电位（DeltaPsi(m)）变化的逆转、caspase-3活性降低、乳酸脱氢酶（LDH）释放和DNA片段化减少均证明了这一点。渥曼青霉素（10 nM）和LY 294002（10 microM）（磷脂酰肌醇-3-激酶，PI3-K的抑制剂）可逆转美金刚对丝裂霉素诱导的LDH释放的抑制作用，提示PI3-K/Akt促生存途径可能是美金刚抗凋亡作用的靶点。低微摩尔浓度的美金刚也可减轻salsolinol和阿霉素诱导的LDH释放和DNA片段化，但仅在salsolinol的情况下，这种作用伴随着caspase-3活性的降低。目前的数据表明，美金刚可减轻各种促凋亡剂的毒性作用，美金刚的细胞保护作用似乎与其对NMDA受体的作用无关，而与其对参与细胞存活/凋亡过程的细胞内途径的影响有关。
