Hsp90 inhibitor HSP990 in very low dose upregulates EAAT2 and exerts potent antiepileptic activity
Hsp90 inhibitor HSP990 in very low dose upregulates EAAT2 and exerts potent antiepileptic activity
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Hsp90 抑制剂 HSP990 在极低剂量下上调 EAAT2 并发挥有效的抗癫痫活性
DOI：
10.7150/thno.44721
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Xu, Qi
中科院分区：
文献类型：
--
作者：
Sha, Longze;Chen, Ting;Xu, Qi
理论基础：癫痫患者存在EAAT2功能障碍或水平降低。我们先前证明了Hsp90抑制剂17AAG通过阻止EAAT2的降解而在颞叶癫痫中起到抗癫痫作用。鉴于17AAG的潜在毒性，本研究旨在寻找一种抑制Hsp90的性能更好、血脑屏障通透性更好、毒性最小的替代Hsp90抑制剂。方法：我们采用细胞筛选和癫痫动物模型，包括小鼠癫痫和阿尔茨海默病模型，以及食蟹猴癫痫模型，评价新的Hsp90抑制剂的抗癫痫作用。结果：在原代培养的星形胶质细胞和正常小鼠中，HSP990以比其他HSP90抑制剂更低的剂量增加EAAT2的水平。在癫痫小鼠中，给予0.1 mg/kg HSP990可上调EAAT2并抑制自发性癫痫发作。此外，在APPswe/PS1dE9转基因阿尔茨海默病模型中，HSP990抑制癫痫发作并改善认知功能。在食蟹猴的颞叶癫痫模型中，口服低剂量HSP990可完全抑制长达12个月的癫痫样放电，没有肝和肾毒性的迹象。结论：这些结果支持了HSP990治疗颞叶癫痫的进一步临床前研究。
Rationale: 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. Methods: 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. Results: 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. Conclusions: These results support further preclinical studies of HSP990 treatment for temporal lobe epilepsy.