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Inhibition of p38 mitogen‐activated protein kinase signaling reduces multidrug transporter activity and anti‐epileptic drug resistance in refractory epileptic rats
Author(s) -
Shao Yiye,
Wang Cuicui,
Hong Zhen,
Chen Yinghui
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13498
Subject(s) - pharmacology , protein kinase a , transporter , epilepsy , multiple drug resistance , p38 mitogen activated protein kinases , refractory (planetary science) , drug , drug resistance , kinase , chemistry , medicine , neuroscience , biology , microbiology and biotechnology , gene , biochemistry , astrobiology
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 p38 MAPK regulates P‐gp expression or drug resistance in refractory epilepsy. This in vivo study examined the effects of p38 MAPK 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 p38 MAPK in electrical and behavioral activity in a rat epilepsy model was studied. The results indicated that p38 MAPK inhibition by SB 202190 reduced P‐gp expression, while increasing AED concentration in the hippocampal extracellular fluid in refractory epileptic rats. SB 202190 also reduced the resistance to AED s in drug‐resistant rats and significantly reduced the severity of seizure activity. These results suggest that p38 MAPK 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.