Abstract
The objective of the present study was to investigate the role of high-mobility group box-1 (HMGB1) in the seizure-induced P-glycoprotein (P-gp) overexpression and the underlying mechanism. Kainic acid (KA)-induced mouse seizure model was used for in vivo experiments. Male C57BL/6 mice were divided into four groups: normal saline control (NS) group, KA-induced epileptic seizure (EP) group, and EP group pretreated with HMGB1 (EP+HMGB1 group) or BoxA (HMGB1 antagonist, EP+BoxA group). Compared to the NS group, increased levels of HMGB1 and P-gp in the brain were observed in the EP group. Injection of HMGB1 before the induction of KA further increased the expression of P-gp while pre-treatment with BoxA abolished this up-regulation. Next, the regulatory role of HMGB1 and its potential involved signal pathways were investigated in mouse microvascular endothelial bEnd.3 cells in vitro. Cells were treated with HMGB1, HMGB1 plus lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) [toll-like receptor 4 (TLR4) antagonist], HMGB1 plus FPS-ZM1 [receptor for advanced glycation end products (RAGE) inhibitor], HMGB1 plus SN50 [nuclear factor-kappa B (NF-κB) inhibitor], or vehicle. Treatment with HMGB1 increased the expression levels of P-gp, TLR4, RAGE and the activation of NF-κB in bEnd.3 cells. These effects were inhibited by the pre-treatment with either LPS-RS or FPS-ZM1, and were abolished by the pre-treatment of SN50 or a combination treatment of both LPS-RS and FPS-ZM1. Luciferase reporter assays showed that exogenous expression of NF-κB p65 increased the promoter activity of multidrug resistance 1a (P-gp-encoding gene) in endothelial cells. These data indicate that HMGB1 contributes to the overexpression of P-gp in mouse epileptic brain tissues via activation of TLR4/RAGE receptors and the downstream transcription factor NF-κB in brain microvascular endothelial cells.
Highlights
Epilepsy is a chronic and devastating neurological disorder characterized by recurrent unprovoked seizures
Our results indicate that high-mobility group box-1 (HMGB1) increases the expression of P-gp in mouse epileptic brain tissues via activation of toll-like receptor 4 (TLR4), receptor for advanced glycation end products (RAGE), and the downstream NF-κB pathway in brain microvascular endothelial cells
Forty-seven mice were randomly divided into four groups, (1) normal saline control group (NS group, n = 11), (2) kainic acid (KA)-induced epileptic seizure group (EP group, n = 12), (3) EP group pretreated with recombinant human HMGB1 (EP+HMGB1 group, n = 12), and (4) EP group pretreated with BoxA
Summary
Epilepsy is a chronic and devastating neurological disorder characterized by recurrent unprovoked seizures. The overexpression of P-glycoprotein (P-gp) induced by seizure activity [2, 3] has been considered to play an important role in the development of drug-refractory epilepsy [4, 5]. It has been documented that the increased level and activity of P-gp on the blood-brain barrier (BBB) were associated with the inflammatory process in epileptic brain. Yin et al [11] reported that extracellular inflammatory molecule high-mobility group box-1 (HMGB1) may promote drug resistance by upregulating the expression of P-gp in human gastric adenocarcinoma cells. HMGB1-mediated inflammatory pathways have been verified to be activated in many seizure animal models and could initiate and expand inflammation in epileptic tissue [12,13,14]. We hypothesize that HMGB1 may be responsible for the upregulated expression of P-gp in the epileptic brain
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