Effects of carbamazepine on the P-gp and CYP3A expression correlated with PXR or NF-κB activity in the bEnd.3 cells.

Autor: Ke XJ; Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, 210029, Nanjing, China., Cheng YF; Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, 210029, Nanjing, China., Yu N; Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, 210029, Nanjing, China., Di Q; Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, 210029, Nanjing, China. Electronic address: diqing1629@163.com.
Jazyk: angličtina
Zdroj: Neuroscience letters [Neurosci Lett] 2019 Jan 18; Vol. 690, pp. 48-55. Date of Electronic Publication: 2018 Oct 09.
DOI: 10.1016/j.neulet.2018.10.016
Abstrakt: Drug-resistant epilepsy (DRE) is present in 20-30% of all patients who develop epilepsy. Growing evidences demonstrated that glutamate released during seizures to increase the brain P-glycoprotein (P-gp) expression. Carbamazepine (CBZ) is known to influence the P-gp and cytochrome P450 (CYP) expression. However, the exact molecular mechanism is still unknown. We investigated that the effects of NF-κB and pregnane X receptor (PXR) activity on P-gp and CYP3A expression in mouse brain endothelial (bEnd.3) cells treated with l-glutamate (mimicking the seizure conditions), CBZ (mimicking the AED treating conditions) or both (l-glutamate plus CBZ) through qPCR and Western blotting assay. Mean fluorescence intensity was used to observe P-gp efflux function by analysis of intracellular Rhodamine123 (Rho123) accumulation. P-gp, CYP3A, PXR and NF-κB p65 were elevated in bEnd.3 cells incubated with l-glutamate, CBZ or CBZ pretreated by l-glutamate for 30 min. Both the mRNA and protein levels of P-gp and CYP3A were remarkably reduced by PXR or NF-κB p65 knock-down by siRNA transfections. The decreased intracellular accumulation of Rho123 suggested that the expression of P-gp was enhanced in bEnd.3 cells. These data suggested that overexpression of P-gp and CYP3A during seizures and treated with CBZ may be regulated by PXR or NF-κB p65 activity and expression, which revealed a mechanism underlying the development of DRE.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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