Neuroprotective effects of selective N-type VGCC blockade on stretch-injury-induced calcium dynamics in cortical neurons.
Neuroprotective effects of selective N-type VGCC blockade on stretch-injury-induced calcium dynamics in cortical neurons.
复制标题
选择性 N 型 VGCC 阻断对皮层神经元拉伸损伤诱导的钙动态的神经保护作用。
DOI：
10.1089/neu.2009.1003
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发表时间：
2010
影响因子：
4.2
通讯作者：
Berman,RobertF
中科院分区：
文献类型：
--
作者：
Shahlaie,Kiarash;Lyeth,BruceG;Gurkoff,GeneG;Muizelaar,JPaul;Berman,RobertF
创伤性脑损伤（TBI）后细胞内钙（[Ca 2 +]i）的急性升高可触发导致神经元功能障碍和死亡的细胞机制。这些过程的机制尚未完全了解，但钙离子通过N型电压门控钙通道（VGCC）流入似乎发挥了核心作用。本研究使用TBI的体外神经元-胶质皮质细胞培养模型检查了损伤后[Ca 2 +]流入、谷氨酸释放和细胞活力丧失的时间过程。还检查了在损伤之前或之后用SNX-185（例如ω-芋螺毒素TVIA）阻断N通道的效果。神经元损伤产生短暂的[Ca 2 +]i升高，谷氨酸释放增加，并导致神经元和胶质细胞死亡。在细胞损伤之前或之后立即给予SNX-185可减少谷氨酸的释放并增加神经元和星形胶质细胞的存活，而延迟治疗并不能改善细胞存活，但显著促进[Ca 2 +]ito基线水平的恢复。新的研究发现，N型VGCCs在损伤诱导的谷氨酸释放和恢复[Ca 2 +]中起着关键作用，这一发现为TBI的临床管理提供了继续研究这种治疗策略的依据。特别是，SNX-185可能代表了一类有效的药物，可以显着保护受损的神经元免受TBI后通常发生的二次损伤。
Acute elevation in intracellular calcium ([Ca2+]i) following traumatic brain injury (TBI) can trigger cellular mechanisms leading to neuronal dysfunction and death. The mechanisms underlying these processes are not completely understood, but calcium influx through N-type voltage-gated calcium channels (VGCCs) appears to play a central role. The present study examined the time course of [Ca2+]iflux, glutamate release, and loss of cell viability following injury using anin vitroneuronal–glial cortical cell-culture model of TBI. The effects of N-channel blockade with SNX-185 (e.g. ω-conotoxin TVIA) before or after injury were also examined. Neuronal injury produced a transient elevation in [Ca2+]i, increased glutamate release, and resulted in neuronal and glial death. SNX-185 administered before or immediately after cell injury reduced glutamate release and increased the survival of neurons and astrocytes, whereas delayed treatment did not improve cell survival but significantly facilitated the return of [Ca2+]ito baseline levels. The new findings that N-type VGCCs are critically involved in injury-induced glutamate release and recovery of [Ca2+]iargue for continued investigation of this treatment strategy for the clinical management of TBI. In particular, SNX-185 may represent an effective class of drugs that can significantly protect injured neurons from the secondary insults that commonly occur after TBI.