目的:本研究通过比较不同药物干预下对GABAARα1、NMDAR1表达的影响,探讨柴贝止痫汤抑制颞叶癫痫发作的分子病理机制。方法:腹腔注射氯化锂-匹罗卡品制成颞叶癫痫模型,通过免疫组织化学方法和显微图像分析技术检测大鼠颞叶、海马的γ-...目的:本研究通过比较不同药物干预下对GABAARα1、NMDAR1表达的影响,探讨柴贝止痫汤抑制颞叶癫痫发作的分子病理机制。方法:腹腔注射氯化锂-匹罗卡品制成颞叶癫痫模型,通过免疫组织化学方法和显微图像分析技术检测大鼠颞叶、海马的γ-氨基丁酸受体(GABAARα1)和谷氨酸受体(NMDAR1)的表达。结果:GABA A Rα1的表达,与空白模型组比较,柴贝止痫汤组、柴贝止痫汤联合卡马西平组癫痫大鼠海马CA1、CA3区及颞叶皮层的GABA A Rα1亚单位表达均明显增强,有高度显著性差异(P<0.01),但柴贝止痫汤组与柴贝止痫汤联合卡马西平组之间无显著性差异(P>0.05)。与正常组比较,空白模型组和卡马西平组癫痫大鼠海马CA1、CA3区及颞叶皮层的GABA A Rα1表达均明显减少,有高度显著性差异(P<0.01)。NMDAR1的表达,与正常组比较,柴贝止痫汤组、柴贝止痫汤联合卡马西平组、卡马西平组、空白模型组海马CA1、CA3区及颞叶皮层的NMDAR1表达均明显增高,有显著性差异(P<0.05),但柴贝止痫汤组、柴贝止痫汤联合卡马西平组、卡马西平组、空白模型组各组之间无显著性差异(P>0.05)。结论:柴贝止痫汤可以提高GABA A Rα1的表达,而对NMDAR1无明显影响。对GABA A Rα1表达的调节是柴贝止痫汤控制癫痫的可能机理之一。展开更多
耳鸣严重影响患者的生活质量,目前认为其产生机制与听觉通路信号改变所引起的神经元可塑性变化有关,其中可能涉及神经元兴奋性和抑制性传导失衡。A型γ-氨基丁酸受体(γ-aminobutyric acid a receptor,GABAAR)和N-甲基-D天冬氨酸受体(N-...耳鸣严重影响患者的生活质量,目前认为其产生机制与听觉通路信号改变所引起的神经元可塑性变化有关,其中可能涉及神经元兴奋性和抑制性传导失衡。A型γ-氨基丁酸受体(γ-aminobutyric acid a receptor,GABAAR)和N-甲基-D天冬氨酸受体(N-methyl-D-aspartic acid receptor,NMDAR)是重要的神经元抑制性和兴奋性受体,NMDAR功能亢进和GABAAR功能抑制可能是耳鸣发生中的关键性事件。钙/钙调蛋白激酶Ⅱ(Ca^2+/calmodulin-dependent protein kinaseⅡ,Ca^2+/CaMKⅡ)是一种丝氨酸/苏氨酸蛋白激酶,介导NMDAR和GABAAR的磷酸化及其相互作用,在神经突触受体活性调节过程中发挥重要作用,并可能参与耳鸣的发生发展过程。本文就Ca^2+/CaMKⅡ介导NMDAR与GABAAR的相互作用及其与耳鸣的关系展开综述,并结合临床试验介绍相关耳鸣治疗最新研究成果,以期为临床耳鸣的治疗提供新的作用靶点和干预思路。展开更多
Although the GABAA receptor(GABAAR)has been proposed as the main action site for sevoflurane,isoflurane,halothane,enflurane,propofol,and benzodiazepines(BZDs),binding of these anesthetics with high-resolution structur...Although the GABAA receptor(GABAAR)has been proposed as the main action site for sevoflurane,isoflurane,halothane,enflurane,propofol,and benzodiazepines(BZDs),binding of these anesthetics with high-resolution structures of the GABAAR have been rarely examined by comparative docking analyses.Moreover,various combinations of ligands on more GABAARs with various subtypes need to be analyzed to understand the elaborate action mechanism of GABAARs better because some GABAA ligands showed specificity toward the distinct subtypes of the GABAAR.Methods:We performed in silico docking analysis to compare the binding modes of sevoflurane,isoflurane,halothane,enflurane,propofol,and BZDs to the GABAAR based on one of the most recently provided 3D structures.We performed the docking analysis and the affinity-based ranking of the binding sites.Results:Our docking studies revealed that isoflurane,halothane,and enflurane docked in an extracellular domain(ECD)on GABAARs,in contrast to sevoflurane.Conclusion:Our results supported a multi-site mechanism for the allosteric modulation of propofol.Propofol was bound to the pore or favored various subsites in the transmembrane domain(TMD).Our result confirmed that different chemically related BZD ligands interact via distinct binding modes rather than by using a common binding mode,as previously suggested.展开更多
文摘目的:本研究通过比较不同药物干预下对GABAARα1、NMDAR1表达的影响,探讨柴贝止痫汤抑制颞叶癫痫发作的分子病理机制。方法:腹腔注射氯化锂-匹罗卡品制成颞叶癫痫模型,通过免疫组织化学方法和显微图像分析技术检测大鼠颞叶、海马的γ-氨基丁酸受体(GABAARα1)和谷氨酸受体(NMDAR1)的表达。结果:GABA A Rα1的表达,与空白模型组比较,柴贝止痫汤组、柴贝止痫汤联合卡马西平组癫痫大鼠海马CA1、CA3区及颞叶皮层的GABA A Rα1亚单位表达均明显增强,有高度显著性差异(P<0.01),但柴贝止痫汤组与柴贝止痫汤联合卡马西平组之间无显著性差异(P>0.05)。与正常组比较,空白模型组和卡马西平组癫痫大鼠海马CA1、CA3区及颞叶皮层的GABA A Rα1表达均明显减少,有高度显著性差异(P<0.01)。NMDAR1的表达,与正常组比较,柴贝止痫汤组、柴贝止痫汤联合卡马西平组、卡马西平组、空白模型组海马CA1、CA3区及颞叶皮层的NMDAR1表达均明显增高,有显著性差异(P<0.05),但柴贝止痫汤组、柴贝止痫汤联合卡马西平组、卡马西平组、空白模型组各组之间无显著性差异(P>0.05)。结论:柴贝止痫汤可以提高GABA A Rα1的表达,而对NMDAR1无明显影响。对GABA A Rα1表达的调节是柴贝止痫汤控制癫痫的可能机理之一。
文摘耳鸣严重影响患者的生活质量,目前认为其产生机制与听觉通路信号改变所引起的神经元可塑性变化有关,其中可能涉及神经元兴奋性和抑制性传导失衡。A型γ-氨基丁酸受体(γ-aminobutyric acid a receptor,GABAAR)和N-甲基-D天冬氨酸受体(N-methyl-D-aspartic acid receptor,NMDAR)是重要的神经元抑制性和兴奋性受体,NMDAR功能亢进和GABAAR功能抑制可能是耳鸣发生中的关键性事件。钙/钙调蛋白激酶Ⅱ(Ca^2+/calmodulin-dependent protein kinaseⅡ,Ca^2+/CaMKⅡ)是一种丝氨酸/苏氨酸蛋白激酶,介导NMDAR和GABAAR的磷酸化及其相互作用,在神经突触受体活性调节过程中发挥重要作用,并可能参与耳鸣的发生发展过程。本文就Ca^2+/CaMKⅡ介导NMDAR与GABAAR的相互作用及其与耳鸣的关系展开综述,并结合临床试验介绍相关耳鸣治疗最新研究成果,以期为临床耳鸣的治疗提供新的作用靶点和干预思路。
文摘Although the GABAA receptor(GABAAR)has been proposed as the main action site for sevoflurane,isoflurane,halothane,enflurane,propofol,and benzodiazepines(BZDs),binding of these anesthetics with high-resolution structures of the GABAAR have been rarely examined by comparative docking analyses.Moreover,various combinations of ligands on more GABAARs with various subtypes need to be analyzed to understand the elaborate action mechanism of GABAARs better because some GABAA ligands showed specificity toward the distinct subtypes of the GABAAR.Methods:We performed in silico docking analysis to compare the binding modes of sevoflurane,isoflurane,halothane,enflurane,propofol,and BZDs to the GABAAR based on one of the most recently provided 3D structures.We performed the docking analysis and the affinity-based ranking of the binding sites.Results:Our docking studies revealed that isoflurane,halothane,and enflurane docked in an extracellular domain(ECD)on GABAARs,in contrast to sevoflurane.Conclusion:Our results supported a multi-site mechanism for the allosteric modulation of propofol.Propofol was bound to the pore or favored various subsites in the transmembrane domain(TMD).Our result confirmed that different chemically related BZD ligands interact via distinct binding modes rather than by using a common binding mode,as previously suggested.
