Proton-sensitive cation channels and ion exchangers in ischemic brain injury: new therapeutic targets for stroke?
Proton-sensitive cation channels and ion exchangers in ischemic brain injury: new therapeutic targets for stroke?
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DOI：
10.1016/j.pneurobio.2013.12.008
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发表时间：
2014-04
影响因子：
6.7
通讯作者：
Sun, Dandan
中科院分区：
文献类型：
--
作者：
Leng, Tiandong;Shi, Yejie;Xiong, Zhi-Gang;Sun, Dandan
缺血性脑损伤是由复杂的细胞机制引起的。目前对急性缺血性卒中的治疗仅限于重组组织型纤溶酶原激活剂(RtPA)溶栓和机械再通。因此，需要更好地了解缺血性脑损伤，以开发更有效的治疗方法。离子稳态的破坏在脑缺血后细胞死亡中起重要作用。谷氨酸受体介导的离子失衡和神经毒性在卒中后脑缺血中已得到充分证实。然而，非NMDA受体依赖的机制，包括酸敏感离子通道1a(ASIC1a)、瞬时受体电位Melastatin 7(TRPM7)和Na+/H+交换异构体1(NHE1)，最近被认为是缺血条件下中枢神经系统离子平衡失调的重要参与者。这些H+敏感通道和/或交换器在神经血管单位的大多数细胞类型中都有表达。这些蛋白的持续激活导致钙、钠、锌等阳离子过量内流，导致脑缺血再灌注损伤。在这篇综述中，我们总结了最近的临床前实验研究结果，这些通道/交换器是如何在体外和体内脑缺血模型中调节的。在这些缺血模型中，阻断或转基因敲除这些蛋白被证明具有神经保护作用。综上所述，这些非NMDA受体依赖的机制可能成为卒中干预的新治疗靶点。
Ischemic brain injury results from complicated cellular mechanisms. The present therapy for acute ischemic stroke is limited to thrombolysis with the recombinant tissue plasminogen activator (rtPA) and mechanical recanalization. Therefore, a better understanding of ischemic brain injury is needed for the development of more effective therapies. Disruption of ionic homeostasis plays an important role in cell death following cerebral ischemia. Glutamate receptor-mediated ionic imbalance and neurotoxicity have been well established in cerebral ischemia after stroke. However, non-NMDA receptor-dependent mechanisms, involving acid-sensing ion channel 1a (ASIC1a), transient receptor potential melastatin 7 (TRPM7), and Na+/H+ exchanger isoform 1 (NHE1), have recently emerged as important players in the dysregulation of ionic homeostasis in the CNS under ischemic conditions. These H+-sensitive channels and/or exchangers are expressed in the majority of cell types of the neurovascular unit. Sustained activation of these proteins causes excessive influx of cations, such as Ca2+, Na+, and Zn2+, and leads to ischemic reperfusion brain injury. In this review, we summarize recent pre-clinical experimental research findings on how these channels/exchangers are regulated in both in vitro and in vivo models of cerebral ischemia. The blockade or transgenic knockdown of these proteins was shown to be neuroprotective in these ischemia models. Taken together, these non-NMDA receptor-dependent mechanisms may serve as novel therapeutic targets for stroke intervention.
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