美金刚保护缺血神经元分子机制的研究

目的 探讨N-甲基-D-天门冬氨酸（NMDA）受体非竞争性抑制剂美金刚（memantine）对脑缺血再灌注（I/R）损伤的影响及其分子机制.方法 制备四动脉结扎（4-VO）大鼠全脑缺血模型.实验分为4组（n=6）：假手术组（sham组）,缺血/再灌注组（I/R组）,美金刚处理组和生理盐水组.在缺血后立刻腹腔注射美金刚或生理盐水.焦油紫染色观察海马CA1区神经元的存活情况,免疫印迹检测大鼠海马中p-ERK1/2的表达.结果 与sham组相比,I/R组神经元死亡增加,p-ERK1/2表达下调;与I/R组相比,美金刚处理组显著降低了神经元的死亡率,同时也明显升高了p-ERK1/2的表达.结论 美金刚抑制了I/R引起的神经元死亡.其机制可能与美金刚抑制突触外NMDA受体的过度激活进而激活ERK通路有关.

Molecular mechanisms for the neuroprotection of memantine against cerebral ischemia/reperfusion injury in rat hippocampal neurons

Objective To investigate the effects and molecular mechanism of memantine, N - methyl - D - aspar-tate （NMDA） receptor noncompetitive inhibitor, on cerebral ischemia/reperfusion （I/R） injury. Methods The animal model of cerebral I/R injury was established via four - vessel occlusion （4 - VO） method in Sprague - Dawley rats, which were randomly assigned to 4 groups （ n = 6 each） ： sham group, I/R group, memantine test group and saline group. Memantine or saline was administered by intraperitoneal injection right after the isehemia. Cresyl violet staining was performed to detect the survival neurons in pyramidal cell layer of the hippocamal CA1 region, and Western blot was used to examine phosphorylated extracellular signal - regulated kinases 1 and 2 （p - ERK1/2） levels. Results Com- pared with sham group,the hippocampal neuron damage in I/R group increased and the expression of p -ERK1/2 was down- regulated. Compared with I/R group, memantine test group could markedly reduce hippocamal neuron damage and promoted the protein expression of p - ERK1/2. Conclusion Memantine inhibites I/R induced neuronal damage and its protective mechanism is that memantine can inhibit excessive activation of extrasynaptic NMDA receptor to activate ERK pathway.