Chronic sleep deprivation promotes drug‐resistant epilepsy via the <scp>BMAL1</scp> ‐ <scp>mTOR</scp> ‐P‐gp axis

OBJECTIVE: The interplay between chronic sleep deprivation and drug-resistant epilepsy (DRE) has gained increasing attention. Brain and muscle Arnt-like protein 1 (BMAL1), which is implicated in sleep disturbance, has an unclear role in DRE. We aimed to investigate the role of BMAL1 in sleep deprivation-induced DRE. METHODS: A pentylenetetrazole (PTZ) kindling epilepsy model was established to explore the impact of chronic sleep deprivation on pharmacoresistance and related molecular expression. BMAL1 was either overexpressed or knocked down in epileptic rats using adeno-associated viral vectors, and pharmacoresistance together with hippocampal protein levels were assessed. Complementary in vitro experiments in brain endothelial cells and astrocytes further evaluated the effects of BMAL1 on Per2, P-S6, and P-gp. RESULTS: Chronic sleep deprivation significantly increased pharmacoresistance, accompanied by reduced BMAL1 and Per2, elevated P-S6, and increased P-glycoprotein (P-gp) expression in the hippocampus. In vitro experiments confirmed that BMAL1 regulates P-gp through the mTOR pathway. In vivo, BMAL1 overexpression attenuated chronic sleep deprivation-induced pharmacoresistance, restoring Per2, inhibiting the mTOR pathway, and reducing P-gp levels. Conversely, BMAL1 knockdown promoted pharmacoresistance in epileptic rats with normal sleep, with decreased Per2, increased P-S6, and elevated P-gp. SIGNIFICANCE: These findings indicate that BMAL1 is an important mediator linking chronic sleep deprivation to pharmacoresistance in epilepsy, and suggest the BMAL1-mTOR-P-gp axis as a potential therapeutic target for drug-resistant epilepsy. PLAIN LANGUAGE SUMMARY: Drug-resistant epilepsy remains a major clinical challenge, and sleep loss increases its risk. We found that chronic sleep loss reduces BMAL1, a protein that helps regulate sleep. In experiments with rats and brain cells, altering BMAL1 levels changed P-glycoprotein via the mTOR pathway. These changes in P-glycoprotein then influenced the response to anti-seizure medicines. The study showed that targeting BMAL1 may be a new treatment for drug-resistant epilepsy.