缺血性神经元损害中非谷氨酸依赖的钙离子毒性机制

普遍认为细胞内Na+和Ca2+进行性堆积能够引起缺血性神经元坏死和凋亡。经典的兴奋性毒性理论认为缺血性神经元死亡是过度激活的离子型谷氨酸受体触发Na+和Ca2+经其进入胞内所致。然而针对兴奋性毒性的NMDA受体拮抗剂在临床试验中的失败,提示可能还存在其他谷氨酸非依赖性Ca2+通路。近年来大量研究发现了一些参与控制Na+和Ca2+内流或外排、负责维持这两种离子动态平衡的整合膜蛋白,包括细胞外酸化时激活的酸感受性离子通道,氧化应激或神经元氧-葡萄糖剥夺时激活的通道TRPM2和TRPM7以及依赖细胞膜两侧电化学梯度的Na+-Ca2+交换体。它们很可能就是引起缺血性神经元死亡的谷氨酸非依赖的钙离子超载机制的分子基础,因而可能代表了更合宜的缺血性卒中治疗的分子靶向。本文通过回顾近几年的研究结果,对它们的结构、功能调节以及在缺血性损伤中的机制作一个评述。

Glutamate-independent Calcium Toxicity in Ischemic Damage

It is widely accepted that the progressive accumulation of intracellular Na and Ca2 is a determinatant factor of neuronal demise during cerebral ischemia by precipitating necrosis and apoptosis of vulunerable neurons.The classic theory of excitotoxicity attributes ischemic neuronal demise to the mere consequence of Na and Ca2 influx through glutamate-ionotropic receptors activated by glutamate which is released into extracellular space during ischemia.Although in the past 2 decades a variety of glutamate receptor antagonists have yielded promising effects in animal modes of cerebral ischemia,they have failed to elicit an expected action in clinical trials.The failure has suggested that glutamate-independent mechanisms of calcium entry during ischemia may exist.A large number of experimental works have suggested that the classic excitotoxicity is an oversimplified interpretation of the chain of events determining ionic derangement in the different phases of brain ischemia.Recently several seminal experimental works have shown that some plasma-membrane integral proteins are involved in control of Na and Ca2 influx or efflux and responsible for maintaining the homeostasis of these two ions,including acid-sensing ion channels activated by extracellular acidosis,TRPM2 and TRPM7,the members of transient receptor potential channels of the melastatin family evoked during neuronal oxygen-glucose deprivation or oxidative stress and gene products of the Na -Ca2 exchanger depending on the ratios of Na and Ca2 oncentration between both sides of cytoplasmic membrane,which can operate either as Ca2 -efflux/Na -influx pathway(forward mode)or as Ca2 -influx/Na -efflux pathway(reverse mode).Indeed,these proteins may provide the molecular basis underlying glutamate-independent Ca2 overload toxicity during ischemic neuronal demise and,most important,may represent more suitable molecular targets for therapeutic intervention.Briefly reviewing recent experimental works offers some insights into their structures,physiological functions,and possible toxic mechanisms in ischemic neuronal damage.