Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, China.
Department of Pharmacy, Children's Hospital of Fudan University, Shanghai, China.
CNS Neurosci Ther. 2023 Jan;29(1):331-343. doi: 10.1111/cns.14008. Epub 2022 Nov 9.
Resistance to valproic acid (VPA) is a major challenge for epilepsy treatment. We aimed to explore the mechanism underlying this resistance.
Pentylenetetrazol-induced chronic epileptic rats were administered VPA (250 mg/Kg) for 14 days; rats with controlled seizure stages (seizure score ≤0) and latent time (latent time ≥0) were considered VPA-responsive, while the others were considered nonresponsive. Differentially expressed genes (DEGs) between the VPA-responsive and nonresponsive rat hippocampus transcriptomes were identified, and their functions were evaluated. The roles of postsynaptic density (PSD) and Homer1 were also determined. Furthermore, a subtype of Homer1 (Homer1b/c) was overexpressed or silenced in HT22 cells to determine its effect on VPA efficacy. Moreover, the membrane levels of mGluR1/5 directly bound to Homer1b/c were assessed.
Overall, 264 DEGs commonly enriched in the PSD between VPA-responsive and nonresponsive rats. Among them, Homer1 was more highly expressed in the hippocampus of nonresponses compared to that of responses. Overexpression of Homer1b/c interrupted VPA efficacy by increasing reactive oxygen species production, lactate dehydrogenase release, and calcium content. Furthermore, it induced the overexpression of mGluR1 and mGluR5.
Overexpression of Homer1b/c influenced VPA efficacy, revealing it could be a target to improve the efficacy of this treatment.
对丙戊酸（VPA）的耐药性是癫痫治疗的主要挑战。我们旨在探索其耐药机制。
戊四氮诱导的慢性癫痫大鼠给予 VPA（250mg/Kg）治疗 14 天；癫痫发作阶段（发作评分≤0）和潜伏期（潜伏期≥0）得到控制的大鼠被认为是 VPA 反应性的，而其他大鼠则被认为是无反应性的。鉴定 VPA 反应性和无反应性大鼠海马转录组之间差异表达的基因（DEGs），并评估其功能。还确定了突触后密度（PSD）和 Homer1 的作用。此外，在 HT22 细胞中过表达或沉默 Homer1 的一种亚型（Homer1b/c），以确定其对 VPA 疗效的影响。此外，还评估了 Homer1b/c 直接结合的 mGluR1/5 的膜水平。
总的来说，264 个 DEGs 在 VPA 反应性和无反应性大鼠的 PSD 中共同富集。其中，Homer1 在无反应大鼠海马中的表达高于反应大鼠。Homer1b/c 的过表达通过增加活性氧产生、乳酸脱氢酶释放和钙含量来干扰 VPA 的疗效。此外，它还诱导 mGluR1 和 mGluR5 的过表达。
Homer1b/c 的过表达影响了 VPA 的疗效，表明它可能是提高该治疗效果的一个靶点。
