title: Pregnane X Receptor Not Nuclear Factor-kappa B Up-regulates P-glycoprotein Expression in the Brain of Chronic Epileptic Rats Induced by Kainic Acid.
abstract: Drug-resistance epilepsy (DRE) is attributed to the brain P-glycoprotein (P-gp) overexpression. We previously reported that nuclear factor-kappa B (NF-κB) played a critical role in regulating P-gp expression at the brain of the acute seizure rats. This study was extended further to investigate the interaction effect of NF-κB and pregnane X receptor (PXR) on P-gp expression at the brain of chronic epileptic rats treated with carbamazepine (CBZ). The chronic epileptic models were induced by the micro-injection of kainic acid (KA) into rats' hippocampus. Subsequently, the successful models were treated with different intervention agents of CBZ; PMA(a non-specific PXR activity inhibitor) or PDTC(a specific NF-κB activity inhibitor) respectively. The expression levels of P-gp and its encoded gene mdr1a/b were significantly up-regulated on the brain of KA-induced chronic epilepsy rats or the epilepsy rats treated with CBZ for 1 week, meanwhile with a high expression of PXR. The treatment of PMA dramatically reduced both PXR and P-gp expressions at the protein and mRNA levels in the chronic epilepsy brain. By compared to the epilepsy model group, the P-gp expression was not markedly attenuated by the inhibition of NF-κB activity with PDTC treatment, nevertheless with a decrease of NF-κB expression in this intervention group. Higher levels of proinflammatory cytokines(IL-1β, IL-6, TNF-α) were found both in the brain tissue and the serum in the epilepsy rats of each group. There was a declined trend of the pro-inflammatory cytokines expression of the PDTC treatment group but with no statistical significance. This study demonstrates for the first time that P-gp up-regulation is due to increase PXR expression in the chronic phase of epilepsy, differently from that NF-κB signaling may induce the P-gp expression in the acute seizure phase. Our results offer insights into the mechanism underlying the development of DRE using or not using CBZ treatment.
authors.affiliation: Department of Neurology, Nanjing Medical University, Affiliated Nanjing Brain Hospital, 210029, Nanjing, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Yu
authors.affiliation: Department of Neurology, Nanjing Medical University, Affiliated Nanjing Brain Hospital, 210029, Nanjing, China.
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Nanjing Medical University, Affiliated Nanjing Brain Hospital, 210029, Nanjing, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Nanjing Medical University, Affiliated Nanjing Brain Hospital, 210029, Nanjing, China.
authors.forename: Yong-Fei
authors.initials: YF
authors.lastname: Cheng
authors.affiliation: Department of Neurology, Nanjing Medical University, Affiliated Nanjing Brain Hospital, 210029, Nanjing, China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Ma
authors.affiliation: Department of Neurology, Nanjing Medical University, Affiliated Nanjing Brain Hospital, 210029, Nanjing, China. diqing@medmail.com.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Di
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis*; D000077297:Pregnane X Receptor; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016328:NF-kappa B; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D007608:Kainic Acid
keywords: Carbamazepine; Drug-resistant epilepsy; Nuclear factor-kappa B; P-glycoprotein; Pregnane X receptor