title: Inhibition of mTOR Pathway by Rapamycin Decreases P-glycoprotein Expression and Spontaneous Seizures in Pharmacoresistant Epilepsy.
abstract: The mammalian target of rapamycin (mTOR) has been demonstrated to mediate multidrug resistance in various tumors by inducing P-glycoprotein (P-gp) overexpression. Here, we investigated the correlation between the mTOR pathway and P-gp expression in pharmacoresistant epilepsy. Temporal cortex specimens were obtained from patients with refractory mesial temporal lobe epilepsy (mTLE) and age-matched controls who underwent surgeries at West China Hospital of Sichuan University between June 2014 and May 2015. We established a rat model of epilepsy kindled by coriaria lactone (CL) and screened pharmacoresistant rats (non-responders) using phenytoin. Non-responders were treated for 4 weeks with vehicle only or with the mTOR pathway inhibitor rapamycin at doses of 1, 3, and 6 mg/kg. Western blotting and immunohistochemistry were used to detect the expression of phospho-S6 (P-S6) and P-gp at different time points (1 h, 8 h, 1 day, 3 days, 1 weeks, 2 weeks, and 4 weeks) after the onset of treatment. Overexpression of P-S6 and P-gp was detected in both refractory mTLE patients and non-responder rats. Rapamycin showed an inhibitory effect on P-S6 and P-gp expression 1 week after treatment in rats. In addition, the expression levels of P-S6 and P-gp in the 6 mg/kg group were significantly lower than those in the 1 mg/kg or the 3 mg/kg group at the same time points (all P < 0.05). Moreover, rapamycin decreased the duration and number of CL-induced seizures, as well as the stage of non-responders (all P < 0.05). The current study indicates that the mTOR signaling pathway plays a critical role in P-gp expression in drug-resistant epilepsy. Inhibition of the mTOR pathway by rapamycin may be a potential therapeutic approach for pharmacoresistant epilepsy.
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, 37th Guoxuexiang Road, Chengdu, Sichuan Province, 610041, China.
authors.forename: Xiaosa
authors.initials: X
authors.lastname: Chi
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, 37th Guoxuexiang Road, Chengdu, Sichuan Province, 610041, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Key Lab of Transplant Engineering and Immunology, MOH, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, 37th Guoxuexiang Road, Chengdu, Sichuan Province, 610041, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, 37th Guoxuexiang Road, Chengdu, Sichuan Province, 610041, China.
authors.forename: Mengqian
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, 37th Guoxuexiang Road, Chengdu, Sichuan Province, 610041, China.
authors.forename: Jinmei
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, 37th Guoxuexiang Road, Chengdu, Sichuan Province, 610041, China. zhoudong66@yahoo.de.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D016022:Case-Control Studies; D000069279:Drug Resistant Epilepsy / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005260:Female; D006801:Humans; D007783:Lactones / Q000633:toxicity; D008297:Male; D010672:Phenytoin / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D007783:Lactones; D010672:Phenytoin; C049836:coriaria lactone; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Epilepsy; P-glycoprotein; Pharmacoresistance; Rat model; mTOR pathway