科研成果: “Hsp90 inhibitor HSP990 in very low dose upregulates EAAT2 and exerts potent antiepileptic activity”(许琪)

发布时间:2020-10-27

导读:许琪课题组于2020年06月在”Theranostics 杂志发表研究论文“Hsp90 inhibitor HSP990 in very low dose upregulates

EAAT2 and exerts potent antiepileptic activity”。文章揭示了低剂量口服Hsp90抑制剂治疗颞叶癫痫食蟹猴模型的机理。

 

文章链接:https://www.thno.org/v10p8415.htm

 

【摘要】Dysfunction or reduced levels of EAAT2 have been documented in epilepsy. We previously demonstrated the antiepileptic effects of Hsp90 inhibitor 17AAG in temporal lobe epilepsy by preventing EAAT2 degradation. Because of the potential toxicities of 17AAG, this study aimed to identify an alternative Hsp90 inhibitor with better performance on Hsp90 inhibition, improved blood-brain barrier penetration and minimal toxicity. We used cell-based screening and animal models of epilepsy, including mouse models of epilepsy and Alzheimer’s disease, and a cynomolgus monkey model of epilepsy, to evaluate the antiepileptic effects of new Hsp90 inhibitors. In both primary cultured astrocytes and normal mice, HSP990 enhanced EAAT2 levels at a lower dose than other Hsp90 inhibitors. In epileptic mice, administration of 0.1 mg/kg HSP990 led to upregulation of EAAT2 and inhibition of spontaneous seizures. Additionally, HSP990 inhibited seizures and improved cognitive functions in the APPswe/PS1dE9 transgenic model of Alzheimer’s disease. In a cynomolgus monkey model of temporal lobe epilepsy, oral administration of low-dose HSP990 completely suppressed epileptiform discharges for up to 12 months, with no sign of hepatic and renal toxicity. These results support further preclinical studies of HSP990 treatment for temporal lobe epilepsy.

 

20220年6月1日,《Theranostics》杂志在线发表了许琪教授团队的研究论文,报道了Hsp90抑制剂的抗癫痫机制。该团队在前期研究中证实Hsp90抑制剂17AAG能够通过提高星形胶质细胞谷氨酸转运体GLT1的蛋白质水平,从而提高星形胶质细胞清除兴奋性神经递质谷氨酸的能力,进而抑制颞叶癫痫小鼠的慢性自发性癫痫发作。本研究发现在颞叶癫痫致癫灶海马内,星形胶质细胞和神经元表达Hsp90的水平存在较大差异,星形胶质细胞仅表达少量的Hsp90,因此在全身给药的情况下,仅需要少量的Hsp90抑制剂就可以抑制星形胶质细胞的Hsp90分子,而对神经元的影响较低,从而降低了化合物的潜在副作用。通过基于原代细胞和小鼠的化合物筛选,我们发现一种名为HSP990的化合物有较好的血脑屏障透过性和对Hsp90的抑制效果,对于癫痫小鼠而言,口服0.1mg/kg的该化合物即可抑制自发性癫痫发作。我们还建立了一种食蟹猴颞叶癫痫模型,证实了长期口服该化合物能够完全抑制食蟹猴大脑的异常癫痫放电,且没有明显的血液毒性。

本研究得到了中国医学科学院医学与健康科技创新工程(项目编号2016-I2M-1-004)和国家自然科学基金的资助。

 

 

 

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