高迁移率族蛋白B1对癫痫大鼠神经损伤及脑P糖蛋白表达的影响及机制
发布时间：2018-12-30 21:47
【摘要】：背景：既往研究证实脑部炎症反应参与了癫痫的发生、发展,与癫痫所致脑组织损伤密切相关。药物转运体P糖蛋白(P-glycoprotein, P-gp)被认为是导致耐药性癫痫(drug-resistant epilepsy, DRE)的重要机制之一,亦与炎性转录因子核因子κB (nuclear factor kappa B, NF-1κB)活化有关。新近研究发现癫痫脑内可产生大量高迁移率族蛋白B1(high mobility group box1, HMGB1), HMGB1作为损伤相关分子模式成员之一,作用于模式识别受体介导免疫炎症反应,调控NF-κB活性,我们前期研究发现癫痫脑内P-gp过表达与NF-κB活化有关,抑制NF-κB活性可下调P-gp表达,那么,HMGB1能否调控P-gp蛋白的表达? 目的：观察拮抗HMGB1对癫痫大鼠癫痫样发作、神经损伤、星型胶质细胞活化的影响,探讨HMGB1是否能通过活化NF-κB调控癫痫大鼠脑P-gp表达。 方法：将雄性SD大鼠分为假手术组(sham组,n=5),癫痫模型组(EP组,n=8),1400ng BoxA(HIMGB1拮抗剂)干预组(B1400组,n=8),140ng BoxA干预组(B140组,n=8),14ng BoxA干预组(B14组,n=8)。侧脑室注射BoxA进行干预,sham组和EP组仅注射NS; BoxA干预后15min向海马注射海人酸(kainic acid, KA)制作癫痫模型,sham组仅注射NS。记录各组大鼠达到Ⅲ级癫痫发作的时间(seizure onset time, SOT)评价癫痫易感性。造模后24h取大鼠脑组织,H.E.染色大体观察脑组织损伤,神经元核抗原(neuronal nuclei, NeuN)染色评价神经损伤程度,胶质纤维酸性蛋白(glial fibrillary acidic protein, GFAP)染色评价星形胶质细胞活化,HMGB1、p-NF-KB-p65、P-gp染色观察BoxA干预对他们表达水平的影响。 主要结果： (1)各BoxA干预组SOT均较EP组延长(P0.05)； (2)各BoxA干预组神经元损伤、丢失程度较EP组轻(P0.05)； (3)EP组星形胶质细胞肿胀,各BoxA干预组GFAP表达少于EP组(P0.05)： (4)5组之间总体比较,HMGB1表达水平差异无统计学意义。EP组海马神经元未见HMGB1表达,而胶质细胞、内皮细胞等HMMGB1表达增加；BoxA干预组神经元有不同程度HMGB1表达,而胶质细胞、内皮细胞HMGB1表达少于EP组； (5)各BoxA干预组P-gp表达少于EP组(P0.05)。 (6)B1400组、B140组p-NF-κB-p65表达少于EP组(P0.05),B14组表达有少于EP组的趋势,但差异未显示统计学意义； 结论：HMGB1拮抗剂BoxA可：降低大鼠的癫痫易感性；减轻神经元损伤,减轻星形胶质细胞肿胀、活化,具有神经保护作用;抑制NF-KB活化,降低P-gP表达。结合我们既往的研究,BoxA可能通过抑制HMGB1,减少其诱导的NF-κB活化及下游P-gp表达。
[Abstract]:Background: previous studies have confirmed that brain inflammation is involved in the occurrence and development of epilepsy, and is closely related to brain tissue damage caused by epilepsy. Drug transporter P-glycoprotein (P-gp) is considered to be one of the important mechanisms leading to drug-resistant epilepsy (drug-resistant epilepsy, DRE), and also related to the activation of inflammatory transcription factor 魏 B (nuclear factor kappa B, NF-1 魏 B. Recently, it has been found that a large number of high mobility group protein B1 (high mobility group box1, HMGB1 can be produced in the epileptic brain. As one of the damage related molecular model members, HMGB1 acts as a pattern recognition receptor mediating immune inflammation and regulating the activity of NF- 魏 B. Our previous study found that the overexpression of P-gp in the epileptic brain is related to the activation of NF- 魏 B, and the inhibition of the activity of NF- 魏 B can down-regulate the expression of P-gp. Can HMGB1 regulate the expression of P-gp protein? Aim: to observe the effects of antagonistic HMGB1 on epileptoid seizure, nerve injury and astrocyte activation in epileptic rats, and to investigate whether HMGB1 can regulate the expression of P-gp in the brain of epileptic rats by activating NF- 魏 B. Methods: male SD rats were divided into three groups: sham operation group (sham group, nong5), epileptic model group (EP group, nong8), 1400ng BoxA (HIMGB1 antagonist) intervention group (B1400, nong8), 140ng BoxA intervention group (B140, nong8), 14ng BoxA intervention group (B14, N8). Intracerebroventricular injection of BoxA was performed in sham group and EP group. After NS; BoxA intervention, 15min injected kainic acid (kainic acid, KA) into hippocampus to make epileptic model, sham group only injected NS.. The time of reaching grade 鈪，
本文编号：2396199
[Abstract]:Background: previous studies have confirmed that brain inflammation is involved in the occurrence and development of epilepsy, and is closely related to brain tissue damage caused by epilepsy. Drug transporter P-glycoprotein (P-gp) is considered to be one of the important mechanisms leading to drug-resistant epilepsy (drug-resistant epilepsy, DRE), and also related to the activation of inflammatory transcription factor 魏 B (nuclear factor kappa B, NF-1 魏 B. Recently, it has been found that a large number of high mobility group protein B1 (high mobility group box1, HMGB1 can be produced in the epileptic brain. As one of the damage related molecular model members, HMGB1 acts as a pattern recognition receptor mediating immune inflammation and regulating the activity of NF- 魏 B. Our previous study found that the overexpression of P-gp in the epileptic brain is related to the activation of NF- 魏 B, and the inhibition of the activity of NF- 魏 B can down-regulate the expression of P-gp. Can HMGB1 regulate the expression of P-gp protein? Aim: to observe the effects of antagonistic HMGB1 on epileptoid seizure, nerve injury and astrocyte activation in epileptic rats, and to investigate whether HMGB1 can regulate the expression of P-gp in the brain of epileptic rats by activating NF- 魏 B. Methods: male SD rats were divided into three groups: sham operation group (sham group, nong5), epileptic model group (EP group, nong8), 1400ng BoxA (HIMGB1 antagonist) intervention group (B1400, nong8), 140ng BoxA intervention group (B140, nong8), 14ng BoxA intervention group (B14, N8). Intracerebroventricular injection of BoxA was performed in sham group and EP group. After NS; BoxA intervention, 15min injected kainic acid (kainic acid, KA) into hippocampus to make epileptic model, sham group only injected NS.. The time of reaching grade 鈪，
本文编号：2396199
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