The Prevention and Reversal of a Phenytoin-Resistant Model by N-acetylcysteine Therapy Involves the Nrf2/P-Glycoprotein Pathway at the Blood-Brain Barrier

The transporter hypothesis is one of the most popular hypotheses of drug-resistant epilepsy (DRE). P-glycoprotein (P-gp), a channel protein at the blood-brain barrier (BBB), plays an important role in the transport of some anti-seizure drugs from brain tissue into vessels, which reduces drug concentrations and diminishes the effects of drug treatment. We performed this study to test whether P-gp is overexpressed in DRE and identify ways to prevent and reverse DRE. In this study, we established a phenytoin (PHT)-resistant mouse model and revealed that P-gp was overexpressed at the BBB in PHT-resistant mice. The P-gp inhibitor nimodipine decreased the resistance of phenytoin. Antioxidative preventive treatment with N-acetylcysteine (NAC) prevented the mice from entering a PHT-resistant state, and NAC therapy tended to reverse PHT resistance into sensitivity. We were also able to induce PHT resistance by activating the Nrf2/P-gp pathway, which indicates that oxidative stress plays an important role in drug resistance. Taken together, these findings suggest that antioxidative therapy may be a promising strategy for overcoming DRE.