Beneficial effect of tetrandrine on refractory epilepsy via suppressing P-glycoprotein

Abstract

Patients with refractory epilepsy are resistance to antiepileptic drugs (AEDs). The mechanisms of drug resistance are varied, but one of them is the overexpression of multidrug transporters, such as P-glycoprotein (P-gp), in the brain. Tetrandrine (TTD) is a bis-benzylisoquinoline alkaloid isolated from the root of Stephania tetrandra (S, Moore) and is found to have a favorable effect against multidrug resistance (MDR) in chemotherapy. However, whether TTD affects AEDs in refractory epilepsy is unknown. In this study, we investigated the change in AED treatment efficacy in doxorubicin-induced drug resistant cells after TTD administration. We also examined the effect of TTD on seizure behaviors in the refractory epileptic rats, specifically the expression of MDR1 mRNA and P-gp protein in the cortex and hippocampus of the refractory epileptic rats. Our results demonstrated that TTD decreased cell resistance to phenytoin and valproate. TTD decreased seizure rate and increased the treatment efficacy of AEDs by reducing the expression of P-gp at mRNA and protein levels in vivo. These data support the use of TTD as an adjuvant drug for treating refractory epilepsy.

KEYWORDS:

• tetrandrine
• refractory epilepsy
• multidrug resistance
• P-glycoprotein
• phenytoin
• valproate

Declaration of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

This work was supported by grants from the Shanghai Committee of Science and Technology (20124234) to YC and a start-up fund of research from Jinshan Hospital (2012-2) to GX.

Authors’ Contributions

Y Chen contributed to the development of project, the design and the performance of experiments. X Xiao performed cell culture and RT-PCR. C Wang performed Western blot. Z Hong and H Jiang participated in the data analysis and wrote the manuscript. G Xu contributed to the data analysis, the generation of figures and the writing of the manuscript. All authors read and approved the final manuscript.