GSK-126 is recognized as an inhibitor of enhancer of zeste homolog-2 (EZH2) activity. Because of its inhibition of EZH2 activation, GSK-126 is considered a potential anti-tumor drug. EZH2 is a histone methyltransferase that catalyzes histone 3 tri-methylation at lysine 27 (H3K27me3), resulting in gene silencing. A previous report showed that decreased H3K27me3 levels in the hippocampus may promote seizure susceptibility, possibly restricting the clinical application of GSK-126. The role of GSK-126 in seizure susceptibility was investigated in this study. We first determined a critical concentration of pentamethazol (PTZ) under which mice exhibit no seizures. We then found that mice pretreated with GSK-126 and injected with the same concentration of PTZ experienced marked convulsions. Peripheral injections of GSK-126 decreased H3K27me3 levels in the hippocampus of mice, while some seizure-related genes (Oasl1, Sox7, armcx5, Ncx3, etc.) were found to be differentially expressed in the hippocampus of those mice . These differences in the expression levels might reflect the crucial role of these genes and related pathways in the promotion of seizure susceptibility. Our results suggest that GSK-126 promotes seizure susceptibility due to its role as an EZH2 inhibitor. These findings may provide evidence to support the development of GSK-126 as a clinical drug.
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This work was financially supported by the National Natural Sciences Foundation of China (grant numbers 81801168, 81802063); the Natural Sciences Foundation of Jiangsu Province (grant number BK20160228); the Natural Science Foundation of the Jiangsu Higher Education Institutions (grant number 18KJB320026); and the Starting Foundation for Talents of Xuzhou Medical University (grant number D2017022).
The authors declare that they have no competing interests.
All animal procedures were approved by the Committee on the Ethics of Animal Experiments of the Xuzhou Medical University (China).
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The Vocalno Plot of different expressed genes. Vocalno Plot indicated up-regulated and down-regulated genes between the GSK-126 and control groups. Up-regulated and down-regulated genes were colored in red and blue, respectively. (PNG 248 kb)
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Wang, Z., Su, Y., Zhuang, D. et al. The Role of EZH2 Inhibitor, GSK-126, in Seizure Susceptibility. J Mol Neurosci 71, 556–564 (2021). https://doi.org/10.1007/s12031-020-01677-7