Alteration of Epileptogenesis Genes
Alteration of Epileptogenesis Genes
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DOI：
10.1016/j.nurt.2009.01.019
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发表时间：
2009-04-01
影响因子：
5.7
通讯作者：
Russek, Shelley J.
中科院分区：
文献类型：
--
作者：
Brooks-Kayal, Amy R.;Raol, Yogendra H.;Russek, Shelley J.
回顾性研究表明，诸如长时间癫痫发作、中风或头部创伤等突发事件会增加以后罹患癫痫的风险。癫痫的发展过程，被称为癫痫发生，与无数基因表达的变化有关。癫痫研究界面临的主要挑战之一是确定哪些变化有助于癫痫发生，哪些可能是代偿性的，哪些可能是非代偿性的。如果要将任何特定基因视为预防或治疗癫痫的治疗靶点，就必须为其建立这一机制。我们的实验室已经检查了与抑制性神经传递相关的基因表达的改变，这些基因表达被认为是癫痫发生的促成因素。GABA A受体介导最快速的突触抑制，在成年动物中，GABA A受体亚基表达和功能的变化在长时间癫痫发作后立即开始（癫痫持续状态[SE]），并在动物成为慢性癫痫时持续。在动物模型中，利用病毒基因转移预防SE后GABA A受体亚基改变可抑制癫痫的发展，表明这些改变直接促进癫痫的发生。最近已经确定了SE后海马GABA A受体亚基差异表达的调节机制，包括CREB-ICER、JAK-STAT、BDNF和Egr3信号通路。靶向改变参与癫痫发生的基因表达的信号通路可能为预防或抑制诱发性损伤后癫痫的发展提供新的治疗方法。
Retrospective studies suggest that precipitating events such as prolonged seizures, stroke, or head trauma increase the risk of developing epilepsy later in life. The process of epilepsy development, known as epileptogenesis, is associated with changes in the expression of a myriad of genes. One of the major challenges for the epilepsy research community has been to determine which of these changes contributes to epileptogenesis, which may be compensatory, and which may be noncontributory. Establishing this for any given gene is essential if it is to be considered a therapeutic target for the prevention or treatment of epilepsy. Our laboratories have examined alterations in gene expression related to inhibitory neurotransmission that have been proposed as contributing factors in epileptogenesis. The GABA A receptor mediates most fast synaptic inhibition, and changes in GABA A receptor subunit expression and function have been reported in adult animals beginning immediately after prolonged seizures (status epilepticus [SE]) and continue as animals become chronically epileptic. Prevention of GABA A receptor subunit changes after SE using viral gene transfer inhibits development of epilepsy in an animal model, suggesting that these changes directly contribute to epileptogenesis. The mechanisms that regulate differential expression of GABA A receptor subunits in hippocampus after SE have recently been identified, and include the CREB-ICER, JAK-STAT, BDNF, and Egr3 signaling pathways. Targeting signaling pathways that alter the expression of genes involved in epileptogenesis may provide novel therapeutic approaches for preventing or inhibiting the development of epilepsy after a precipitating insult.