Abstracts

Rationale: The mammalian target of rapamycin (mTOR) has been proved to mediate multidrug resistance in tumor by inducing P-glycoprotein (Pgp) overexpression. Therefore, we treated the pharmacoresistant epilepsy rat model with the mTOR inhibitor, rapamycin, to investigate the potential effect of mTOR on pharmacoresistant mechanism in epilepsy.Methods: We established a pharmacoresistant epilepsy SD rat model by repeated injections of coriaria lactone, and kindled rats were treated with rapamycin at different doses of 1, 3, and 10 mg/kg every other day for four weeks. Rapamycin-treated rats were sacrificed at various time points (0h,1h,8h,24h,3d,7d,14d, and 28d) after rapamycin administration for Western blotting and immunohistochemical analysis.Results: The overexpression of both phosopho-S6 (P-S6) and Pgp were detected in kindled rats compared to normal rats. For rapamycin-treated rats, the P-S6 increased in the first 24h, peaked at 8h, decreased after 24h, and returned to normal by 14d (all P<0.05). The Pgp showed the same pattern of change with P-S6. After 28d, the expressive levels of P-S6 and Pgp in kindled rats with rapamycin were significantly lower than kindled rats without treatment (all P<0.05). In addition, the expression of P-S6 and Pgp in 10mg/kg group was significantly less than those in 1mg/kg and 3mg/kg group at the same time point (all P<0.05). Results in the current study indicated that the modulating effect of rapamycin on P-S6 and Pgp is dose-dependent.Conclusions: The current study indicates that the rapamycin down-regulates the expression of P-glycoprotein by mTOR signaling pathway, and the inhibitory effect is dose-dependent. Therefore, mTOR signaling pathway has a potential role in drug-resistant mechanisms, and may be a potential drug target for pharmacoresistant epilepsy.