Autophagy associated with the efficacy of valproic acid in PTZ-induced epileptic rats

Abstract 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.