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.

MiR‐181b inhibits P38/JNK signaling pathway to attenuate autophagy and apoptosis in juvenile rats with kainic acid‐induced epilepsy via targeting TLR4

“…More importantly, P38/JNK signaling pathway was reported to be correlated with epilepsy, which was activated in rat hippocampus postkainic acid‐induced seizure . Besides, in refractory epileptic rats, suppressing p38 signaling weakened multidrug transporter activity and antiepileptic drug resistance . Last but not least, there were no significant alterations after rats accepted injection of miR‐181b agomir and LPS (TLR4 activator).…”

The Sphingosine 1‐Phosphate Analogue FTY720 Alleviates Seizure‐induced Overexpression of P‐Glycoprotein in Rat Hippocampus

“…Potschka's group suggested that inhibition of COX‐2 can attenuate abnormal expression of P‐gp, strengthen brain delivery of AEDs and reduce seizure frequency in epileptic rats . Besides NF‐κB signalling, the p38 MAPK pathway might also be involved in regulating P‐gp expression in refractory epilepsy .…”

Clinical significance of the phosphorylation of MAPK and protein expression of cyclin D1 in human osteosarcoma tissues

“…As the axis of several types of signal channels, mitogen-activated protein kinase (MAPK) cascade activation is a key member in the receipt of signals, which are transferred and carried by membrane receptors into the nucleus (6,7), which is key to numerous signaling channels associated with cell proliferation.…”