可乐定对原代培养大鼠皮质神经元氧糖剥夺及兴奋性毒性损伤的改善作用
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摘要
目的:研究可乐定(clonidine)(1、3、10μM)对原代培养大鼠皮质神经元氧糖剥夺损伤及NMDA损伤的改善作用及其机制的探讨;研究可乐定对正常大鼠海马CA1区突触可塑性的影响。方法:采用原代培养第八天的大鼠皮质神经元,预给予可乐定(1,3,10μM)通过化学性缺氧、孵育液缺糖的方法建立神经元的OGD损伤模型;通过NMDA浓度为100μM的无镁孵育液孵育12h,建立神经元的NMDA损伤模型。神经元损伤程度采用MTT染色法和检测LDH的释放量来进行评价。可乐定(50,100μg/kg)对正常大鼠海马突触可塑性的影响通过记录大鼠海马Schaffer纤维-CA1通路的长时程增强(LTP)而实现。结果:1可乐定对OGD损伤原代培养大鼠皮质神经元MTT染色及LDH释放量的影响:正常对照组MTT染色细胞百分存活率为(100±32.12)%,LDH的百分释放量为(100±37.51)%。与正常组比较,OGD组MTT染色A570明显减小,显著降低细胞存活率(p<0.01);LDH的释放量则显著升高(p<0.01)。与OGD组比较,可乐定(1,3,10μM)可以明显升高A570,显著提高细胞的百分存活率;LDH的释放量也显著降低。2可乐定对NMDA损伤原代培养大鼠皮质神经元MTT染色及LDH释放量的影响:正常对照组MTT染色细胞百分存活率为(100±19.46)%,LDH的百分释放量为(100±18.46)%。与正常组比较,模型组MTT染色A570明显减小,细胞存活率显著降低(p<0.01);LDH的释放量显著升高(p<0.01)。可乐定(1,3,10μM)可以明显升高A570,显著提高细胞的百分存活率;LDH的释放量也显著降低。3可乐定对正常大鼠海马CA1区突触可塑性的影响:正常生理盐水对照组在给予强直刺激后120min内PS相对幅值稳定在基线值的(163±44.03)%(n=5),即说明LTP诱导成功。可乐定高、低剂量组(50,100μg/kg)均使LTP被明显抑制,其PS幅值在强直刺激后各时间点均显著低于正常组(p<0.01),低、高剂量在强直刺激后120min内PS相对幅值平均分别为(132.74±6.72)%(n=5);(118±11.01)%(n=5);高剂量组强直刺激后120min内PS相对幅值显著低于低剂量组(p<0.05)。结论:1.可乐定(1,3,10μM)对OGD损伤及兴奋毒性损伤的原代培养大鼠皮质神经元具有明显的保护作用,该作用可能与降低谷氨酸受体过度兴奋引起的兴奋性中毒有关。2.可乐定(50,100μg/kg)可以抑制大鼠海马Schaffer纤维-CA1通路的长时程增强(LTP),改变突触可塑性,影响学习记忆功能。
Aims: The present study was carried out to determine the neuroprotective effect of clonidine (1, 3, 10μM) and the related mechanisms on primary cultured rat cortical neurons exposed to oxygen-glucose deprivation (OGD) and N-methyl-D-aspartate (NMDA). In addition, to observe the effect of clonidine (50, 100μg/kg) on the synaptic plasticity in normal rat hippocampal CA1 region is another aim. Methods: The 8th day of primary cultures of cortical neurons was suffered from OGD induced by depriving oxygen and glucose in the solution of incubation for 4h, while the neurons were exposed to Earle’s solution in which Mg2+ is free but containing 100μM NMDA for 12h to induce another kind of injury. Clonidine (1, 3, 10μM) was added 24h before OGD or NMDA injury. Neuronal injury was detected by MTT staining method and measurement of lactate dehydrogenase (LDH) release. The effect of clonidine (50, 100μg/kg) on the synaptic plasticity in normal rat was assessed by recording the changes of LTP after that the high frequencey stimulation (HFS) was given to Schaffer. Results: 1. Effect of clonidine on primary cultured rat cortical neurons exposed to OGD in MTT staining and the release of LDH: in the group of control, the percentage of suvival rate of neurons was (100±32.12) %; and the percent of LDH release was (100±37.51) %. Compared with control, there was a significant reduction in A570 in the group of OGD (p<0.01); meanwhile, there was a notable increase in the release of LDH (p<0.01). In groups given different concentration of clonidine, the percent of survival neurons was much greater than the injured group, and the release of LDH decreased greatly as well. 2. Effect of clonidine on primary cultured rat cortical neurons exposed to NMDA in MTT staining and the release of LDH: in the group of control, the survival rate of neurons was (100±19.46) %, and the percent of LDH release was (100±18.46) %. Compared with control, there was a significant reduction in A570 in the group of NMDA (p<0.01); meanwhile, the percent of LDH release experienced a sharply growth (p<0.01). In groups given different concentration of clonidine, the percent of survival neurons was much greater than the injured group, and the release of LDH decreased greatly as well. 3. The effect of clonidine on the synaptic plasticity in normal rat hippocampal CA1 region: in vehicles, in 120min after HFS, the value of population spike (PS) sustained around (163±44.03) % of the value of baseline, which indicated that LTPs were induced successfully. In rats administered clonidine at the dosages of 50 and 100μg/kg, values of PS were significantly reduced than vehicles (p<0.01), which were (132.74±6.72) %, (118±11.01) % respectively. In adition, within 120min after HFS, the values of PS of rats administered high dose of clonidine were notably lower than that of ones given the low dosage (p<0.05). Conclusion: 1. Clonidine can exert notable neuroprotection against OGD/NMDA-induced injury in primary cultured cortical neurons. The machenism is probably though attenuating excitotoxicity which is mediated by NMDA receptor partly. 2. Clonidine can depress synaptic plasticity of hippocampal CA1 region in normal rat through the model of LTP, and this probably mediated working memory.
Aims: The present study was carried out to determine the neuroprotective effect of clonidine (1, 3, 10μM) and the related mechanisms on primary cultured rat cortical neurons exposed to oxygen-glucose deprivation (OGD) and N-methyl-D-aspartate (NMDA). In addition, to observe the effect of clonidine (50, 100μg/kg) on the synaptic plasticity in normal rat hippocampal CA1 region is another aim. Methods: The 8th day of primary cultures of cortical neurons was suffered from OGD induced by depriving oxygen and glucose in the solution of incubation for 4h, while the neurons were exposed to Earle’s solution in which Mg2+ is free but containing 100μM NMDA for 12h to induce another kind of injury. Clonidine (1, 3, 10μM) was added 24h before OGD or NMDA injury. Neuronal injury was detected by MTT staining method and measurement of lactate dehydrogenase (LDH) release. The effect of clonidine (50, 100μg/kg) on the synaptic plasticity in normal rat was assessed by recording the changes of LTP after that the high frequencey stimulation (HFS) was given to Schaffer. Results: 1. Effect of clonidine on primary cultured rat cortical neurons exposed to OGD in MTT staining and the release of LDH: in the group of control, the percentage of suvival rate of neurons was (100±32.12) %; and the percent of LDH release was (100±37.51) %. Compared with control, there was a significant reduction in A570 in the group of OGD (p<0.01); meanwhile, there was a notable increase in the release of LDH (p<0.01). In groups given different concentration of clonidine, the percent of survival neurons was much greater than the injured group, and the release of LDH decreased greatly as well. 2. Effect of clonidine on primary cultured rat cortical neurons exposed to NMDA in MTT staining and the release of LDH: in the group of control, the survival rate of neurons was (100±19.46) %, and the percent of LDH release was (100±18.46) %. Compared with control, there was a significant reduction in A570 in the group of NMDA (p<0.01); meanwhile, the percent of LDH release experienced a sharply growth (p<0.01). In groups given different concentration of clonidine, the percent of survival neurons was much greater than the injured group, and the release of LDH decreased greatly as well. 3. The effect of clonidine on the synaptic plasticity in normal rat hippocampal CA1 region: in vehicles, in 120min after HFS, the value of population spike (PS) sustained around (163±44.03) % of the value of baseline, which indicated that LTPs were induced successfully. In rats administered clonidine at the dosages of 50 and 100μg/kg, values of PS were significantly reduced than vehicles (p<0.01), which were (132.74±6.72) %, (118±11.01) % respectively. In adition, within 120min after HFS, the values of PS of rats administered high dose of clonidine were notably lower than that of ones given the low dosage (p<0.05). Conclusion: 1. Clonidine can exert notable neuroprotection against OGD/NMDA-induced injury in primary cultured cortical neurons. The machenism is probably though attenuating excitotoxicity which is mediated by NMDA receptor partly. 2. Clonidine can depress synaptic plasticity of hippocampal CA1 region in normal rat through the model of LTP, and this probably mediated working memory.
引文
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