Involvement of hypoxia-inducible factor-1 alpha in the upregulation of P-glycoprotein in refractory epilepsy

To explore the involvement of hypoxia-inducible factor-1 alpha (HIF-1α) in the upregulation of P-glycoprotein (P-gp) in refractory epilepsy. Brain tissue specimens were collected and analyzed for expression of HIF-1α and P-gp using an immunohistochemical (IHC) staining method in both refractory epilepsy group and control group. Correlation between HIF-1α and P-gp expression level in refractory epilepsy group was analyzed. Then, a hypoxia cell model was established by simulating the nerve cell hypoxic microenvironment in the human U251 cell line using cobalt chloride (CoCl2). Western blot analysis was used to detect expression levels of HIF-1α and P-gp in the hypoxic cell model. Finally, expression of HIF-1α and P-gp was detected using real-time quantitative PCR and Western blot, respectively, after U251 hypoxic model cells were infected with HIF-1α siRNA. IHC scores of HIF-1α and P-gp in refractory epilepsy group were significantly higher than that in control group. In addition, the expression of HIF-1α was positively correlated with the expression of P-gp in refractory epilepsy group. Expression levels of HIF-1α and P-gp in U251 cells cultured with 250 µmol/L CoCl2 for 48 hours were significantly higher than that in controls. After transfection with siRNA targeting HIF-1α, expressions of HIF-1α and P-gp at mRNA and protein level were decreased, respectively, in the hypoxia cell model. HIF-1α may be involved in the upregulation of P-gp in refractory epilepsy through inducement of P-gp expression. Therefore, activation of the HIF-1α/P-gp pathway is one hypothesis proposed to explain the pathogenesis of refractory epilepsy.