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.

GSK-126 被认为是 zeste homolog-2 (EZH2) 活性增强剂的抑制剂。由于其抑制 EZH2 激活，GSK-126 被认为是一种潜在的抗肿瘤药物。EZH2 是一种组蛋白甲基转移酶，可在赖氨酸 27 (H3K27me3) 处催化组蛋白 3 三甲基化，从而导致基因沉默。之前的一份报告表明，海马体中 H3K27me3 水平的降低可能会促进癫痫发作的易感性，可能会限制 GSK-126 的临床应用。本研究调查了 GSK-126 在癫痫易感性中的作用。我们首先确定了五甲唑 (PTZ) 的临界浓度，在该浓度下小鼠不会出现癫痫发作。然后我们发现用 GSK-126 预处理并注射相同浓度 PTZ 的小鼠出现明显的抽搐。外周注射 GSK-126 降低了小鼠海马中 H3K27me3 的水平，而一些癫痫相关基因（Oasl1、Sox7、armcx5、Ncx3 等）被发现在这些小鼠的海马中差异表达。这些表达水平的差异可能反映了这些基因和相关途径在促进癫痫易感性中的关键作用。我们的结果表明 GSK-126 由于其作为 EZH2 抑制剂的作用而促进癫痫易感性。这些发现可能为支持 GSK-126 作为临床药物的开发提供证据。表达水平的这些差异可能反映了这些基因和相关途径在促进癫痫易感性中的关键作用。我们的结果表明 GSK-126 由于其作为 EZH2 抑制剂的作用而促进癫痫易感性。这些发现可能为支持 GSK-126 作为临床药物的开发提供证据。这些表达水平的差异可能反映了这些基因和相关途径在促进癫痫易感性中的关键作用。我们的结果表明 GSK-126 由于其作为 EZH2 抑制剂的作用而促进癫痫易感性。这些发现可能为支持 GSK-126 作为临床药物的开发提供证据。