Valproic acid (VPA) is a widely used antiepileptic drugs. Patients who are non-responsive to VPA often present to the clinic; however, the mechanism of resistance is unclear. In this study, we found that responder and non-responder pentylenetetrazole-induced chronic epileptic rats had no significant differences in VPA concentrations in their plasma and brain tissues. Furthermore, through an RNA-sequence method, we identified 334 differentially expressed genes between VPA-responsive and non-responsive rats, while 21 pathways were enriched. Interestingly, 16 pathways, including the phagosome pathway, were commonly enriched compared to those in patients. We used transmission electron microscopy and immunofluorescence microscopy to further assess the level of autophagy in responder and non-responder rats. Non-responders had more autophagic vacuoles and an increased level of LC3B expression. Furthermore, epileptic rats that were previously administered 3-methyadenine (an inhibitor of autophagy) exhibited a slight increase in VPA efficacy. In conclusion, autophagy was associated with the efficacy of VPA.

丙戊酸（VPA）是一种广泛使用的抗癫痫药物。对 VPA 无反应的患者经常出现在诊所；然而，耐药机制尚不清楚。在本研究中，我们发现反应者和非反应者戊四唑诱导的慢性癫痫大鼠血浆和脑组织中的 VPA 浓度没有显着差异。此外，通过 RNA 序列方法，我们在 VPA 反应和非反应大鼠之间鉴定了 334 个差异表达基因，同时富集了 21 个通路。有趣的是，与患者体内的通路相比，包括吞噬体通路在内的 16 条通路通常更富集。我们使用透射电子显微镜和免疫荧光显微镜来进一步评估响应者和非响应者大鼠的自噬水平。无反应者有更多的自噬泡和增加的 LC3B 表达水平。此外，先前给予 3-甲腺嘌呤（一种自噬抑制剂）的癫痫大鼠表现出 VPA 功效略有增加。总之，自噬与 VPA 的疗效有关。