中国神经再生研究(英文版) ›› 2016, Vol. 11 ›› Issue (1): 75-76.doi: 10.4103/1673-5374.169630

• 观点:脑损伤修复保护与再生 • 上一篇    下一篇

神经细胞间隙连接蛋白与缺血性神经元死亡

  

  • 收稿日期:2015-10-19 出版日期:2016-01-15 发布日期:2016-01-15

Role of neuronal gap junctions in NMDA receptor-mediated excitotoxicity and ischemic neuronal death

Andrei B. Belousov, Joseph D. Fontes   

  1. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA (Belousov AB)
    Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA (Fontes JD)
  • Received:2015-10-19 Online:2016-01-15 Published:2016-01-15
  • Contact: Andrei B. Belousov, Ph.D.,abelousov@kumc.edu.

摘要:

连接蛋白36表达会在大部分神经元损伤症状内,一般为损伤后1-2小时迅速上升,其中包括缺血、创伤性脑损伤、脊髓损伤、癫痫和炎症。药理封锁或遗传消除含连接蛋白36缝隙连接会使脑缺血,创伤性脑损伤和癫痫动物模型中的神经元死亡显著减少,并能够减轻N-甲基-D-天冬氨酸受体介导的兴奋性毒性。这表明了神经元间隙连接在神经元死亡机制中的关键作用。文章主要讨论了以下3个问题:连接蛋白36表达的变化会直接影响到神经元死亡吗?连接蛋白36对神经元死亡造成的影响取决于神经元之间缝隙连接复合通道的活性吗,还是与通道无关?神经元半通道与神经元死亡有关吗?并为神经间隙连接在N-甲基-D-天冬氨酸受体依赖性的兴奋性中毒和缺血性神经元死亡的相关机制提供了深入了解。由于N-甲基-D-天冬氨酸受体拮抗剂作为神经保护剂的临床试验在很大程度上都失败了,因此该研究表明了开发新神经保护剂的另一个重要治疗目标可以是神经元缝隙连接耦合。

Abstract:

In the mammalian CNS coupling of neurons by gap junctions and the expression of neuronal gap junction protein, connexin 36 (Cx36) rapidly increase (usually during 1-2 hours) following a wide range of neuronal injuries, including ischemia, traumatic brain injury (TBI), spinal cord injury, epilepsy and inflammation. Pharmacological blockade or genetic elimination of Cx36-containing gap junctions dramatically reduce neuronal death in animal models of ischemia, TBI and epilepsy and prevent NMDA receptor (NMDAR)-mediated excitotoxicity. This suggests a critical role for neuronal gap junctions in the mechanisms of neuronal death. In our recent study, we addressed the following three questions. Are changes in the expression of Cx36 directly affect neuronal death? Is the contribution of Cx36 to neuronal death depends on channel activity of gap junctional complexes among neurons or it is channel-independent? Do neuronal hemichannels contribute to neuronal death? In conclusion, this study provided insight into the mechanisms of contribution of neuronal gap junctions in NMDAR-dependent excitotoxicity and ischemic neuronal death. Because clinical trials for NMDAR antagonists as neuroprotective agents largely failed, the study suggested that another important therapeutic target for the development of new neuroprotective agents can be neuronal gap junction coupling.