Role of glutamate excitotoxicity and glutamate transporter EAAT2 in epilepsy: Opportunities for novel therapeutics development.
Role of glutamate excitotoxicity and glutamate transporter EAAT2 in epilepsy: Opportunities for novel therapeutics development.
复制标题
DOI：
10.1016/j.bcp.2021.114786
复制
发表时间：
2021-11
影响因子：
5.8
通讯作者：
Fontana ACK
中科院分区：
文献类型：
--
作者：
Green JL;Dos Santos WF;Fontana ACK
癫痫是一种复杂的神经系统综合征，其特征是神经元过度兴奋和突然同步放电引起的癫痫发作。星形胶质细胞功能受损导致谷氨酸兴奋毒性已被认为在癫痫的发病机制中发挥着关键作用。虽然有 26 种药物作为抗癫痫药物上市，但目前的治疗方法都不能改变疾病，因为它们只能抑制癫痫发作，而不能抑制癫痫的发生和进展。兴奋性氨基酸转运蛋白 (EAAT) 对于维持低细胞外谷氨酸浓度和防止兴奋性毒性至关重要。当细胞外谷氨酸浓度上升到异常水平时，谷氨酸受体过度激活以及随后钙过量流入突触后神经元可以触发细胞死亡途径。在这篇综述中，我们讨论以 EAAT2（中枢神经系统中主要的谷氨酸转运蛋白）为目标，作为开发癫痫疗法的一种有前景的方法。事实证明，EAAT2 通过转录和翻译调节上调可在体内成功减少自发性复发性癫痫发作并提供神经保护作用。调节 EAAT2 活性的另一种方法是通过正变构调节 (PAM)。 EAAT2 的新型 PAM 最近已被鉴定并正在开发中，代表了一种有前途的新癫痫疗法进展方法。
Epilepsy is a complex neurological syndrome characterized by seizures resulting from neuronal hyperexcitability and sudden and synchronized bursts of electrical discharges. Impaired astrocyte function that results in glutamate excitotoxicity has been recognized to play a key role in the pathogenesis of epilepsy. While there are 26 drugs marketed as anti-epileptic drugs no current treatments are disease modifying as they only suppress seizures rather than the development and progression of epilepsy. Excitatory amino acid transporters (EAATs) are critical for maintaining low extracellular glutamate concentrations and preventing excitotoxicity. When extracellular glutamate concentrations rise to abnormal levels, glutamate receptor overactivation and the subsequent excessive influx of calcium into the post-synaptic neuron can trigger cell death pathways. In this review we discuss targeting EAAT2, the predominant glutamate transporter in the CNS, as a promising approach for developing therapies for epilepsy. EAAT2 upregulation via transcriptional and translational regulation has proven successful in vivo in reducing spontaneous recurrent seizures and offering neuroprotective effects. Another approach to regulate EAAT2 activity is through positive allosteric modulation (PAM). Novel PAMs of EAAT2 have recently been identified and are under development, representing a promising approach for the advance of novel therapeutics for epilepsy.
登录
查看更多内容
影响因子：
4.2
作者：
Carbone M;Duty S;Rattray M
通讯作者：
Rattray M
影响因子：
6.1
作者：
Bjornsen, L. P.;Eid, T.;de Lanerolle, N. C.
通讯作者：
de Lanerolle, N. C.
影响因子：
56.9
作者：
Bellocchio, EE;Reimer, RJ;Edwards, RH
通讯作者：
Edwards, RH
影响因子：
64.8
作者：
Canul-Tec JC;Assal R;Cirri E;Legrand P;Brier S;Chamot-Rooke J;Reyes N
通讯作者：
Reyes N
影响因子：
4.2
作者：
Chapman, AG
通讯作者：
Chapman, AG