Contribution of apoptosis-associated signaling pathways to epileptogenesis: lessons from Bcl-2 family knockouts.
Contribution of apoptosis-associated signaling pathways to epileptogenesis: lessons from Bcl-2 family knockouts.
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DOI：
10.3389/fncel.2013.00110
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发表时间：
2013
影响因子：
5.3
通讯作者：
Engel T
中科院分区：
文献类型：
--
作者：
Henshall DC;Engel T
神经元细胞死亡是许多脑损伤的病理生理学结果，其触发癫痫，并被认为是癫痫发生的一个因果因素。癫痫发作诱导的神经元死亡的特征是兴奋性毒性坏死和癫痫相关的信号通路，包括Bcl-2基因家族的多个成员的激活。单个Bcl-2家族成员被删除的小鼠的可用性提供了确定它们是否在体内神经元死亡和癫痫发生中具有因果作用的方法。研究表明，Bcl-2家族的多个成员在癫痫持续状态后被激活，并且Bcl-2家族的八种不同敲除的癫痫发作和损伤表型现在已经被表征。某些促凋亡成员的损失，包括彪马，保护免受缺血诱导的神经元死亡，而抗凋亡的Mcl-1和Bcl-w的损失增强海马损伤。值得注意的是，两个促细胞凋亡成员巴克和Bmf的缺失导致更多的脑损伤，而Bid的缺失没有影响，表明某些Bcl-2家族蛋白在癫痫脑损伤中的作用不同于它们在其他应激源或非CNS组织中的作用。值得注意的是，Puma缺陷型小鼠在癫痫持续状态后发生较少的自发性癫痫发作，表明神经保护可以直接通过保护神经元网络或间接地（例如通过限制对神经元死亡的反应性神经胶质增生和促炎反应）来保护功能抑制。总之，这些研究支持癫痫相关的分子机制控制神经元死亡作为癫痫发生的一个组成部分，这可能是有针对性的，以防止脑损伤，认知缺陷和减轻癫痫诱发脑损伤后综合征的严重程度。
Neuronal cell death is a pathophysiological consequence of many brain insults that trigger epilepsy and has been implicated as a causal factor in epileptogenesis. Seizure-induced neuronal death features excitotoxic necrosis and apoptosis-associated signaling pathways, including activation of multiple members of the Bcl-2 gene family. The availability of mice in which individual Bcl-2 family members have been deleted has provided the means to determine whether they have causal roles in neuronal death and epileptogenesis in vivo. Studies show that multiple members of the Bcl-2 family are activated following status epilepticus and the seizure and damage phenotypes of eight different knockouts of the Bcl-2 family have now been characterized. Loss of certain pro-apoptotic members, including Puma, protected against seizure-induced neuronal death whereas loss of anti-apoptotic Mcl-1 and Bcl-w enhanced hippocampal damage. Notably, loss of two putatively pro-apoptotic members, Bak and Bmf, resulted in more seizure-damage while deletion of Bid had no effect, indicating the role of certain Bcl-2 family proteins in epileptic brain injury is distinct from their contributions following other stressors or in non-CNS tissue. Notably, Puma-deficient mice develop fewer spontaneous seizures after status epilepticus suggesting neuroprotection may preserve functional inhibition, either directly by preserving neuronal networks or indirectly, for example by limiting reactive gliosis and pro-inflammatory responses to neuronal death. Together, these studies support apoptosis-associated molecular mechanisms controlling neuronal death as a component of epileptogenesis which might be targetable to protect against seizure-damage, cognitive deficits and mitigate the severity of syndrome following epilepsy-precipitating injuries to the brain.
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影响因子：
3.3
作者：
Engel, T.;Hatazaki, S.;Tanaka, K.;Prehn, J. H. M.;Henshall, D. C.
通讯作者：
Henshall, D. C.
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通讯作者：
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作者：
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