Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou, China; Department of Pharmacy, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China.
Department of Pharmacy, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China.
Brain Res. 2020 Oct 15;1745:146923. doi: 10.1016/j.brainres.2020.146923. Epub 2020 Jun 3.
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 反应不佳的患者经常会到诊所就诊；然而，其耐药机制尚不清楚。在这项研究中，我们发现对戊四氮诱导的慢性癫痫大鼠 VPA 浓度在其血浆和脑组织中无显著差异。此外，通过 RNA 测序方法，我们鉴定了 334 个在 VPA 反应性和非反应性大鼠之间差异表达的基因，同时富集了 21 个通路。有趣的是，与患者相比，有 16 个通路是共同富集的，包括吞噬体途径。我们使用透射电子显微镜和免疫荧光显微镜进一步评估反应性和非反应性大鼠的自噬水平。非反应性大鼠有更多的自噬空泡和 LC3B 表达水平增加。此外，先前给予 3-甲基腺嘌呤（自噬抑制剂）的癫痫大鼠 VPA 的疗效略有增加。总之，自噬与 VPA 的疗效有关。
