抑制星形胶质细胞Hsp90-GLT1的抗癫痫机制研究

发布时间：2018-11-04 11:01

【摘要】：大脑内的兴奋性神经递质"谷氨酸"的异常累积是导致癫痫发作的主要原因。星形胶质细胞可以通过谷氨酸转运蛋白1(GLT-1/EAAT2)来清除胞外谷氨酸,终止神经兴奋性传导。病理证据表明,GLT-1的"缺失"是导致谷氨酸异常累积的重要原因,但原因尚不清楚。本课题组近期的研究发现,致癫灶的星形胶质细胞中过量表达的Hsp90β通过将GLT-1募集到20S蛋白酶体的方式促进GLT-1的蛋白降解。Hsp90抑制剂能够阻止GLT-1的过度降解,显著提高GLT-1的蛋白水平,并增强星形胶质细胞对体外谷氨酸的清除能力。我们对颞叶癫痫模型小鼠开展的治疗性研究发现,Hsp90抑制剂17AAG具有显著的抗癫痫效果,长期用药可大幅降低自发性癫痫发作频率(平均抑制效果73.4%),提高无癫痫发作天数,同时能够缓解星形胶质细胞增生的病理现象。本工作拓展了癫痫发病的分子病理机制,也为颞叶癫痫等难治性癫痫的治疗提供了新的思路。
[Abstract]:Abnormal accumulation of excitatory neurotransmitter glutamate in the brain is the main cause of epileptic seizures. Astrocytes can scavenge extracellular glutamate through glutamate transporter 1 (GLT-1/EAAT2) and terminate excitatory conduction. Pathological evidence suggests that the "deletion" of GLT-1 is an important cause of abnormal glutamate accumulation, but the cause remains unclear. Our recent study found that overexpression of Hsp90 尾 in astrocytes of epileptogenic foci promoted the protein degradation of GLT-1 by raising GLT-1 into 20s proteasome. Hsp90 inhibitor could prevent the excessive degradation of GLT-1. The protein level of GLT-1 was significantly increased and the ability of astrocytes to clear glutamate in vitro was enhanced. In our therapeutic study of temporal lobe epilepsy model mice, we found that Hsp90 inhibitor 17AAG had significant antiepileptic effect, and long-term administration of 17AAG could significantly reduce the frequency of spontaneous epileptic seizures (the average inhibitory effect was 73.4%). Increasing the number of days without epileptic attack and alleviating the pathological phenomenon of astrocyte proliferation. This work extends the molecular pathological mechanism of epilepsy and provides a new idea for the treatment of intractable epilepsy such as temporal lobe epilepsy.
【作者单位】：中国医学科学院基础医学研究所北京协和医学院基础学院中国医学院神经科学中心;
【分类号】：R742.1

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