Theranostics 2020; 10(18):8415-8429. doi:10.7150/thno.44721

Research Paper

Hsp90 inhibitor HSP990 in very low dose upregulates EAAT2 and exerts potent antiepileptic activity

Longze Sha1,3*, Ting Chen1*, Yu Deng1, Tingfu Du2,3, Kaili Ma2,3, Wanwan Zhu1,3, Yan Shen1, Qi Xu1,3✉

1. State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.
2. Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, 650118, China.
3. Neuroscience center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
*These authors contributed equally to the work.

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Citation:
Sha L, Chen T, Deng Y, Du T, Ma K, Zhu W, Shen Y, Xu Q. Hsp90 inhibitor HSP990 in very low dose upregulates EAAT2 and exerts potent antiepileptic activity. Theranostics 2020; 10(18):8415-8429. doi:10.7150/thno.44721. Available from http://www.thno.org/v10p8415.htm

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Abstract

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.

Keywords: Temporal lobe epilepsy, Hsp90, EAAT2, HSP990