Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm.
Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm.
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DOI：
10.1016/j.pathophys.2007.09.009
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发表时间：
2007-12-01
期刊：
影响因子：
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通讯作者：
Mongin, Alexander A
中科院分区：
文献类型：
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作者：
Mongin, Alexander A
脑组织损伤的机制与兴奋性毒性现象密切相关，兴奋性毒性被定义为由于兴奋性神经递质谷氨酸和天冬氨酸受体的过度激活而导致神经细胞的损伤或死亡。在生理条件下，离子型谷氨酸受体介导兴奋性神经传递和突触可塑性过程。在缺血时，神经元和神经胶质细胞持续的病理性谷氨酸释放导致这些受体的长时间激活，导致大量的去极化和胞浆内钙超载。细胞内高水平的Ca(2+)激活了许多降解过程，根据代谢状态的不同，这些过程会导致神经细胞立即或延迟死亡。这一传统的观点已经被大量的观察所扩展，这些观察表明，在谷氨酸毒性的发展过程中，涉及氯(-)通道和几种非通道转运蛋白，如Na(+)、K(+)、2Cl(-)共转运蛋白、Na(+)/H(+)交换器和Na(+)/Ca(2+)交换器。其中一些离子转运体通过促进病理性细胞肿胀和坏死性细胞死亡来增加组织损伤，而另一些离子转运体则有助于细胞质钙(2+)的长期积累。这篇简短的综述旨在说明各种离子转运过程的失调如何结合在一起形成一场‘完美风暴’，破坏神经细胞的离子稳态，最终导致神经细胞的不可逆转的损伤和死亡。还简要讨论了作为卒中治疗干预靶点的个体转运体的临床相关性。
The mechanisms of brain tissue damage in stroke are strongly linked to the phenomenon of excitotoxicity, which is defined as damage or death of neural cells due to excessive activation of receptors for the excitatory neurotransmitters glutamate and aspartate. Under physiological conditions, ionotropic glutamate receptors mediate the processes of excitatory neurotransmission and synaptic plasticity. In ischemia, sustained pathological release of glutamate from neurons and glial cells causes prolonged activation of these receptors, resulting in massive depolarization and cytoplasmic Ca(2+) overload. High cytoplasmic levels of Ca(2+) activate many degradative processes that, depending on the metabolic status, cause immediate or delayed death of neural cells. This traditional view has been expanded by a number of observations that implicate Cl(-) channels and several types of non-channel transporter proteins, such as the Na(+),K(+),2Cl(-) cotransporter, Na(+)/H(+) exchanger, and Na(+)/Ca(2+) exchanger, in the development of glutamate toxicity. Some of these ion transporters increase tissue damage by promoting pathological cell swelling and necrotic cell death, while others contribute to a long-term accumulation of cytoplasmic Ca(2+). This brief review is aimed at illustrating how the dysregulation of various ion transport processes combine in a 'perfect storm' that disrupts neural ionic homeostasis and culminates in the irreversible damage and death of neural cells. The clinical relevance of individual transporters as targets for therapeutic intervention in stroke is also briefly discussed.