黄芩素对大鼠海马CA1区突触可塑性的影响及其机制
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摘要
第一部分黄芩素对大鼠海马CA1区突触可塑性的影响
目的:黄芩素(Baicalein,BAI)是从黄芩的干燥根中提取的主要黄酮之一。以往研究表明BAI具有抗炎、抗病毒、抗氧化损伤等药理作用,并能改善脑损伤引起的认知障碍。已有报道黄酮类天然化合物可提高动物的认知能力、增强LTP。但黄芩总黄酮的单体黄芩素是否可改善正常动物的认知能力,影响LTP尚未见报道。本研究旨在观察BAI对大鼠海马脑片CA1区长时程增强(Long-term potentiation,LTP)的影响,并进一步探讨其作用机制。方法:急性分离大鼠海马脑片,通过细胞外记录海马CA1区场电位的方法,观察BAI对海马CA1区基础突触传递、突触前反应、长时程增强的影响。结果:低浓度BAI不影响基础突触传递,高浓度(100μmol/L)BAI显著增强fEPSP的斜率和幅度。10μmol/L BAI显著增强海马CA1区的LTP。10μmol/L BAI作用脑片后,反映突触前反应的两个指标PPR和输入-输出反应没有显著变化。N-甲基-D-天冬氨酸(NMDA)受体阻断剂APV可完全阻断BAI易化LTP的作用;胞内钙离子螯合剂BAPTA-AM可显著抑制BAI增强LTP的作用。L型电压依赖性钙通道阻断剂维拉帕米不能阻断BAI增强LTP的作用。结论:BAI能增强海马CA1区NMDA受体依赖的LTP,且该作用是钙离子依赖的。
第二部分黄芩素对大鼠海马CA1区突触可塑性相关蛋白质表达的影响
目的:神经颗粒素(Ng)是神经元内与钙调蛋白(CaM)结合的一种蛋白质,其主要作用是调节Ca2+和钙/钙调蛋白(Ca2+/CaM)介导的信号通路。钙/钙调蛋白依赖性蛋白激酶Ⅱ(CaMKII)是脑内Ca2+/CaM依赖的激酶之一,调节神经元的很多功能,与学习记忆密切相关。CaMKII第286位苏氨酸有一个自身磷酸化位点,通过自身磷酸化CaMKII可介导短暂胞内钙离子浓度([Ca2+]i)升高触发的某些生理功能的长时程改变。已知CaMKII是NMDA受体依赖的LTP所必需的。本研究旨在观察Ng、CaMKII在BAI易化LTP的过程中的作用,进一步探讨BAI增强LTP的机制。方法:利用western blot方法,场电位记录结束后提取CA1区蛋白质,观察BAI对海马脑片CA1区CaMKⅡ,pCaMKⅡ,Ng,pNg表达的影响。结果:高频刺激(HFS)可增加脑片pCaMKⅡ和pNg的表达;10μmol/L BAI可增加HFS脑片pCaMKⅡ和pNg的表达。结论:BAI易化LTP的作用与其增加pCaMKⅡ和pNg表达有关。
Part 1. Effects of BAI on synaptic plasticity of CA1 subfield in rat hippocampal slices
Background: Baicalein is one of the major flavonoids extracted from the dried root of Scutellaria baicalensis Georgi (Huangqin). It has been widely used as an antibacterial and antiviral agent. Previous research has demonstrated that baicalein is a free radical scavenger and a selective inhibitor of 12-lipoxygenase. Total flavonoids isolated from Scutellaria baicalensis Georgi has been shown to improve memory impairment and chemical neuronal damage. Recently, several studies have demonstrated effects of mixtures of flavonoids on learning and memory and long-term potentiation (LTP). However, no detailed studies have been performed concerning the impact of BAI on LTP of CA1 subfield in rat hippocampal slices. The aim of the current investigation was to characterize the role of BAI on long-term potentiation (LTP) in the CA1 region of rat hippocampal slices and to elucidate the molecular sequence of events leading to these changes. Methods: Using hippocampal slice preparations and electrophysiology recording, we investigated the effects of BAI on fEPSP, PPR, I/O curve and LTP of CA1 subfield. Results: BAI did not affect basal synaptic transmission in normal slices at low concentration. However, administration of 100μmol/L BAI enhanced fEPSP in CA1 subfield significantly. LTP was enhanced by incubation of 10μmol/L BAI significantly. We found that administration of BAI did not alter the presynaptic glutamate release in response to both single pulse and tetanic stimulation. NMDA receptor antagonist APV blocked BAI-facilitated LTP. Pre-treatment of slices with verapamil had no significant effect on BAI-facilitated LTP. Calcium chelator BAPTA-AM prevented BAI-facilitated LTP significantly. Conclusion: These findings demonstrate that the natural product BAI facilitated LTP is dependent on NMDA receptors and [Ca2+] i.
Part 2. Effects of BAI on plasticity-related proteins of CA1 subfield in rat hippocampal slices
Background: Neurogranin (Ng) is a neural-specific CaM-binding protein that is a substrate for PKC. Ng is implicated in the modulation of Ca2+ and Ca2+/CaM-mediated signaling pathways. CaMKII is a major class of Ca2+/calmodulin-dependent protein kinases in the brain that contributes to various neuronal processes, associated with learning and memory formation. Interestingly, CaMKII contains an autophosphorylation site at threonine 286, the phosphorylation of which generates a Ca2+/CaM-independent, autonomously active form of CaMKII (pThr286-CaMKII). Through this mechanism, pCaMKII can evoke prolonged physiological responses triggered by transient increases in [Ca2+]i. It is clear that CaMKII is required as a mediator for NMDA receptor-dependent LTP. The aim of this study is to test the role of Ng and CaMKII in BAI-facilitated LTP. Methods: Western blot technique was employed to analyze the changes of CaMKII and Ng levels after BAI treatment and HFS stimulation. Results: 10μmol/L BAI increased the ratio of pCaMKIIα/CaMKII and pNg/Ng after HFS stimulation, measured in the total homogenate of hippocampal CA1 area. Conclusion: BAI-facilitated LTP was associated with increases in the expression of pCaMKII and pNg.
目的:黄芩素(Baicalein,BAI)是从黄芩的干燥根中提取的主要黄酮之一。以往研究表明BAI具有抗炎、抗病毒、抗氧化损伤等药理作用,并能改善脑损伤引起的认知障碍。已有报道黄酮类天然化合物可提高动物的认知能力、增强LTP。但黄芩总黄酮的单体黄芩素是否可改善正常动物的认知能力,影响LTP尚未见报道。本研究旨在观察BAI对大鼠海马脑片CA1区长时程增强(Long-term potentiation,LTP)的影响,并进一步探讨其作用机制。方法:急性分离大鼠海马脑片,通过细胞外记录海马CA1区场电位的方法,观察BAI对海马CA1区基础突触传递、突触前反应、长时程增强的影响。结果:低浓度BAI不影响基础突触传递,高浓度(100μmol/L)BAI显著增强fEPSP的斜率和幅度。10μmol/L BAI显著增强海马CA1区的LTP。10μmol/L BAI作用脑片后,反映突触前反应的两个指标PPR和输入-输出反应没有显著变化。N-甲基-D-天冬氨酸(NMDA)受体阻断剂APV可完全阻断BAI易化LTP的作用;胞内钙离子螯合剂BAPTA-AM可显著抑制BAI增强LTP的作用。L型电压依赖性钙通道阻断剂维拉帕米不能阻断BAI增强LTP的作用。结论:BAI能增强海马CA1区NMDA受体依赖的LTP,且该作用是钙离子依赖的。
第二部分黄芩素对大鼠海马CA1区突触可塑性相关蛋白质表达的影响
目的:神经颗粒素(Ng)是神经元内与钙调蛋白(CaM)结合的一种蛋白质,其主要作用是调节Ca2+和钙/钙调蛋白(Ca2+/CaM)介导的信号通路。钙/钙调蛋白依赖性蛋白激酶Ⅱ(CaMKII)是脑内Ca2+/CaM依赖的激酶之一,调节神经元的很多功能,与学习记忆密切相关。CaMKII第286位苏氨酸有一个自身磷酸化位点,通过自身磷酸化CaMKII可介导短暂胞内钙离子浓度([Ca2+]i)升高触发的某些生理功能的长时程改变。已知CaMKII是NMDA受体依赖的LTP所必需的。本研究旨在观察Ng、CaMKII在BAI易化LTP的过程中的作用,进一步探讨BAI增强LTP的机制。方法:利用western blot方法,场电位记录结束后提取CA1区蛋白质,观察BAI对海马脑片CA1区CaMKⅡ,pCaMKⅡ,Ng,pNg表达的影响。结果:高频刺激(HFS)可增加脑片pCaMKⅡ和pNg的表达;10μmol/L BAI可增加HFS脑片pCaMKⅡ和pNg的表达。结论:BAI易化LTP的作用与其增加pCaMKⅡ和pNg表达有关。
Part 1. Effects of BAI on synaptic plasticity of CA1 subfield in rat hippocampal slices
Background: Baicalein is one of the major flavonoids extracted from the dried root of Scutellaria baicalensis Georgi (Huangqin). It has been widely used as an antibacterial and antiviral agent. Previous research has demonstrated that baicalein is a free radical scavenger and a selective inhibitor of 12-lipoxygenase. Total flavonoids isolated from Scutellaria baicalensis Georgi has been shown to improve memory impairment and chemical neuronal damage. Recently, several studies have demonstrated effects of mixtures of flavonoids on learning and memory and long-term potentiation (LTP). However, no detailed studies have been performed concerning the impact of BAI on LTP of CA1 subfield in rat hippocampal slices. The aim of the current investigation was to characterize the role of BAI on long-term potentiation (LTP) in the CA1 region of rat hippocampal slices and to elucidate the molecular sequence of events leading to these changes. Methods: Using hippocampal slice preparations and electrophysiology recording, we investigated the effects of BAI on fEPSP, PPR, I/O curve and LTP of CA1 subfield. Results: BAI did not affect basal synaptic transmission in normal slices at low concentration. However, administration of 100μmol/L BAI enhanced fEPSP in CA1 subfield significantly. LTP was enhanced by incubation of 10μmol/L BAI significantly. We found that administration of BAI did not alter the presynaptic glutamate release in response to both single pulse and tetanic stimulation. NMDA receptor antagonist APV blocked BAI-facilitated LTP. Pre-treatment of slices with verapamil had no significant effect on BAI-facilitated LTP. Calcium chelator BAPTA-AM prevented BAI-facilitated LTP significantly. Conclusion: These findings demonstrate that the natural product BAI facilitated LTP is dependent on NMDA receptors and [Ca2+] i.
Part 2. Effects of BAI on plasticity-related proteins of CA1 subfield in rat hippocampal slices
Background: Neurogranin (Ng) is a neural-specific CaM-binding protein that is a substrate for PKC. Ng is implicated in the modulation of Ca2+ and Ca2+/CaM-mediated signaling pathways. CaMKII is a major class of Ca2+/calmodulin-dependent protein kinases in the brain that contributes to various neuronal processes, associated with learning and memory formation. Interestingly, CaMKII contains an autophosphorylation site at threonine 286, the phosphorylation of which generates a Ca2+/CaM-independent, autonomously active form of CaMKII (pThr286-CaMKII). Through this mechanism, pCaMKII can evoke prolonged physiological responses triggered by transient increases in [Ca2+]i. It is clear that CaMKII is required as a mediator for NMDA receptor-dependent LTP. The aim of this study is to test the role of Ng and CaMKII in BAI-facilitated LTP. Methods: Western blot technique was employed to analyze the changes of CaMKII and Ng levels after BAI treatment and HFS stimulation. Results: 10μmol/L BAI increased the ratio of pCaMKIIα/CaMKII and pNg/Ng after HFS stimulation, measured in the total homogenate of hippocampal CA1 area. Conclusion: BAI-facilitated LTP was associated with increases in the expression of pCaMKII and pNg.
引文
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