Inhibition of USP15 Prevent Glutamate-Induced Oxidative Damage by Activating Nrf2/HO-1 Signaling Pathway in HT22 Cells

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Oxidative stress has been identified as the significant mediator in epilepsy, which is a chronic disorder in central nervous system. About 30% of epilepsy patients are refractory to antiepileptic drug treatment. However, the underlying mechanism of oxidative damage in epilepsy needs further investigation. In our study, we first find that ubiquitin-specific peptidase 15 (USP15) expression was upregulated in a pentylenetetrazole (PTZ) kindled rat model of epilepsy. Silencing USP15 protected against glutamate-mediated neuronal cell death, and inhibited the high expression levels of cleaved caspase-3. Knockout of USP15 significantly reduced intracellular reactive oxygen species (ROS) levels and enhanced superoxide dismutase (SOD) activity in HT22 cells under the exposure to glutamate treatment. Furthermore, USP15 inhibition induced nuclear factor erythroid-derived 2-related factor2 (Nrf2) nuclear translocation and promoted protein expression level of heme oxygenase (HO-1). Taken together, our findings first reveal a role of USP15 in the pathogenesis of epilepsy, and silencing USP15 in vitro protects against glutamate-mediated cytotoxicity in HT22 cells. Pharmacological inhibition of USP15 may alleviate epileptic seizures via fighting against oxidative damage, providing a novel antiepileptic target.

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We gratefully acknowledge the financial support of this research by Shanghai Science & Technology Research Program (14411972200), Scientific Research Project of Shanghai Municipal Health Bureau (20134067).

Author information

GB and XC conceived and designed the study. XC and FL performed the experiments. XC contributed to the statistical analyses. GB and XC wrote the manuscript. All authors have reviewed and approved the final manuscript.

Correspondence to Guanshui Bao.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the Ethics Committee of Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, (China) or practice at which the studies were conducted.

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Chen, X., Bao, G. & Liu, F. Inhibition of USP15 Prevent Glutamate-Induced Oxidative Damage by Activating Nrf2/HO-1 Signaling Pathway in HT22 Cells. Cell Mol Neurobiol (2020) doi:10.1007/s10571-020-00789-3

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  • Epilepsy
  • Glutamate
  • Oxidative stress
  • USP15
  • Nrf2/HO-1 pathway