title: Inhibition of p38 mitogen-activated protein kinase signaling reduces multidrug transporter activity and anti-epileptic drug resistance in refractory epileptic rats.
abstract: It is widely recognized that P-glycoprotein (P-gp) mediates drug resistance in refractory epilepsy. However, the molecular mechanism underlying the up-regulation of P-gp expression remains unclear. Our previous studies have demonstrated that p38 mitogen-activated protein kinase (MAPK) regulates P-gp expression in cultured K562 cells. However, a lack of in vivo research leaves unanswered questions regarding whether p38MAPK regulates P-gp expression or drug resistance in refractory epilepsy. This in vivo study examined the effects of p38MAPK on the expression of P-gp and mdr1 in the rat brain and quantified antiepileptic drug (AED) concentrations in the hippocampal extracellular fluid. In addition, the role of p38MAPK in electrical and behavioral activity in a rat epilepsy model was studied. The results indicated that p38MAPK inhibition by SB202190 reduced P-gp expression, while increasing AED concentration in the hippocampal extracellular fluid in refractory epileptic rats. SB202190 also reduced the resistance to AEDs in drug-resistant rats and significantly reduced the severity of seizure activity. These results suggest that p38MAPK could participate in drug resistance in refractory epilepsy through the regulation of P-gp. We show that the specific inhibitor of p38MAPK could down-regulate the expression of multidrug transporter (P-glycoprotein) in blood-brain barrier, increase the concentration of antiepileptic drugs in the hippocampal extracellular fluid and reduce anti-epileptic drug resistance in refractory epileptic rats. We propose that the p38MAPK signaling pathway participates in drug resistance in refractory epilepsy through the regulation of P-glycoprotein expression.
authors.affiliation: Department of Neurology, Jinshan Hospital, Fudan University, Shanghai, China.|Department of Neurology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yiye
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Neurology, Jinshan Hospital, Fudan University, Shanghai, China.|Department of Neurology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurology, Shanghai Medical College, Fudan University, Shanghai, China.|Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Hong
authors.affiliation: Department of Neurology, Jinshan Hospital, Fudan University, Shanghai, China.|Department of Neurology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000187:drug effects; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000927:Anticonvulsants; D048051:p38 Mitogen-Activated Protein Kinases
keywords: P-glycoprotein; SB202190; drug resistance; p38MAPK; refractory epilepsy