淫羊藿苷调控中枢胆碱能神经环路乙酰化内稳态改善小鼠卒中后认知障碍的研究
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摘要
目的：本研究旨在观察补肾中药淫羊藿有效提取成分——淫羊藿苷对卒中后认知障碍小鼠的治疗效果,并进一步探讨其机制,以期为临床用药提供客观依据,并为开发治疗卒中后认知障碍的中药新药提供科学基础。
方法：选用ICR清洁级雄性小鼠,利用大脑中动脉栓塞(MCAO)法制作卒中后认知障碍模型。造模成功后,将认知障碍小鼠随机分为卒中后认知障碍+蒸馏水组、卒中后认知障碍+30mg/kg淫羊藿苷组、卒中后认知障碍+60mg/kg淫羊藿苷组和卒中后认知障碍+120mg/kg淫羊藿苷组,每组25只,加上假手术+蒸馏水组、假手术+60mg/kg淫羊藿苷组,每组各25只,共6组150只。用药各组小鼠根据要求按照不同的体重分别灌入相应剂量的淫羊藿苷,非用药组灌入相应的蒸馏水,每日一次,共28天。28天后,利用水迷宫方法检测小鼠认知功能,并利用分子生物学、病理学等方法检测小鼠中枢胆碱能神经环路功能改变情况和乙酰化内稳态改变情况等。
结果：淫羊藿苷可以减少卒中后认知障碍小鼠的逃避潜伏期和搜索距离,该效应有剂量依赖性；淫羊藿苷可增加卒中后认知障碍小鼠中枢胆碱能神经环路中乙酰胆碱的含量,以及增加胆碱乙酰基转移酶的mRNA和蛋白的表达,且该效应有剂量依赖性；淫羊藿苷可增加卒中后认知障碍小鼠中枢胆碱能神经环路中组蛋白H3乙酰化水平,该效应有剂量依赖性,但不改变环路中组蛋白H4乙酰化水平；淫羊藿苷改善卒中后认知障碍小鼠中枢胆碱能神经环路中p-CREB蛋白的下降,并该效应有剂量依赖性。
结论：
(1)短暂性大脑中动脉栓塞模型可以引起小鼠认知功能障碍,同时伴有中枢胆碱能神经环路中乙酰胆碱和胆碱乙酰基转移酶的减少；
(2)在卒中后认知障碍模型中,中枢胆碱能神经环路中组蛋白乙酰化内稳态是有失衡的,同时,环路中相应脑区中p-CREB蛋白表达水平也是相应降低的；
(3)淫羊藿苷可以改善卒中后认知障碍小鼠的认知功能,提高中枢胆碱能神经环路中乙酰胆碱和胆碱乙酰基转移酶水平,改善失衡的组蛋白乙酰化内稳态。而淫羊藿苷的这些作用很可能与它能改善环路中相应脑区中p-CREB降低有关。
Objective This research is aim to observe the curative effect of icarrin(ICA), a prenylated flavonol glycoside derived from Herba Epimedii that is one of traditional Chinese medicines with tonifying Kidney effect, in mice with post-stroke cognitive impairment(PSCI). The results of this work will provide the objective evidences for clincal medication and pursue a way for developing the new Chinese herbal drugs about PSCI.
Methods PSCI in the mice was induced using the middle cerebral artery occlusion (MCAO) model with modifications. These mice and other sham-operated mice were randomly divided into6groups:sham-operated+placebo group (Sham group), sham-operated+ICA group (60mg/kg), PSCI model+placebo group, PSCI model+ICA group (30,60, or120mg/kg). Every group had25qualified mice. Sham-operated+placebo group and PSCI model+placebo group were administered distilled water intragastrically for28days. Sham-operated+ICA group and PSCI model+ICA group were administered with indicated doses of ICA by gavage daily for28days. After28days, cognitive function of mice was detected by morris water maze test,and the changes of the function and the acetylated homeostasis of the central cholinergic circuits of mice also were detected by molecular biology and pathology.
Results ICA can reduce the escape latency and searching distance of the mice with PSCI and this effect has dose-dependent.ICA can increase ACh levels and the ChAT mRNA and protein of expression levels in the central cholinergic circuits of the mice with PSCI, and this effect has dose-dependent. ICA can increase the expression levels of Ac-H3in the central cholinergic circuits of the mice with PSCI, and this effect has dose-dependent. But after the administration of the various doses of ICA, the expression level of Ac-H4did not change in any of the groups. ICA can improve the decline of the phosphorylated CREB in cholinergic circuits of mice with PSCI.
Conclusion (1) Transient MCAO caused cognitive dysfunction of mice which is associated with the decreased levels of ACh and CHAT in the central cholinergic circuits;
(2) The histone acetylation homeostasis of the central cholinergic circuits were impaired in post-stroke impairment model. At the same time, the levels of p-CREB in the corresponding brain regions were declined accordingly;
(3) ICA improved cognitive function of mice with PSCI, enhanced the levels of ACh and ChAT in the central cholinergic circuits and improved the damage of acetylated homeostasis. All these were related to the role of ICA that reversed this decline of the CREB phosphorylation.
方法：选用ICR清洁级雄性小鼠,利用大脑中动脉栓塞(MCAO)法制作卒中后认知障碍模型。造模成功后,将认知障碍小鼠随机分为卒中后认知障碍+蒸馏水组、卒中后认知障碍+30mg/kg淫羊藿苷组、卒中后认知障碍+60mg/kg淫羊藿苷组和卒中后认知障碍+120mg/kg淫羊藿苷组,每组25只,加上假手术+蒸馏水组、假手术+60mg/kg淫羊藿苷组,每组各25只,共6组150只。用药各组小鼠根据要求按照不同的体重分别灌入相应剂量的淫羊藿苷,非用药组灌入相应的蒸馏水,每日一次,共28天。28天后,利用水迷宫方法检测小鼠认知功能,并利用分子生物学、病理学等方法检测小鼠中枢胆碱能神经环路功能改变情况和乙酰化内稳态改变情况等。
结果：淫羊藿苷可以减少卒中后认知障碍小鼠的逃避潜伏期和搜索距离,该效应有剂量依赖性；淫羊藿苷可增加卒中后认知障碍小鼠中枢胆碱能神经环路中乙酰胆碱的含量,以及增加胆碱乙酰基转移酶的mRNA和蛋白的表达,且该效应有剂量依赖性；淫羊藿苷可增加卒中后认知障碍小鼠中枢胆碱能神经环路中组蛋白H3乙酰化水平,该效应有剂量依赖性,但不改变环路中组蛋白H4乙酰化水平；淫羊藿苷改善卒中后认知障碍小鼠中枢胆碱能神经环路中p-CREB蛋白的下降,并该效应有剂量依赖性。
结论：
(1)短暂性大脑中动脉栓塞模型可以引起小鼠认知功能障碍,同时伴有中枢胆碱能神经环路中乙酰胆碱和胆碱乙酰基转移酶的减少；
(2)在卒中后认知障碍模型中,中枢胆碱能神经环路中组蛋白乙酰化内稳态是有失衡的,同时,环路中相应脑区中p-CREB蛋白表达水平也是相应降低的；
(3)淫羊藿苷可以改善卒中后认知障碍小鼠的认知功能,提高中枢胆碱能神经环路中乙酰胆碱和胆碱乙酰基转移酶水平,改善失衡的组蛋白乙酰化内稳态。而淫羊藿苷的这些作用很可能与它能改善环路中相应脑区中p-CREB降低有关。
Objective This research is aim to observe the curative effect of icarrin(ICA), a prenylated flavonol glycoside derived from Herba Epimedii that is one of traditional Chinese medicines with tonifying Kidney effect, in mice with post-stroke cognitive impairment(PSCI). The results of this work will provide the objective evidences for clincal medication and pursue a way for developing the new Chinese herbal drugs about PSCI.
Methods PSCI in the mice was induced using the middle cerebral artery occlusion (MCAO) model with modifications. These mice and other sham-operated mice were randomly divided into6groups:sham-operated+placebo group (Sham group), sham-operated+ICA group (60mg/kg), PSCI model+placebo group, PSCI model+ICA group (30,60, or120mg/kg). Every group had25qualified mice. Sham-operated+placebo group and PSCI model+placebo group were administered distilled water intragastrically for28days. Sham-operated+ICA group and PSCI model+ICA group were administered with indicated doses of ICA by gavage daily for28days. After28days, cognitive function of mice was detected by morris water maze test,and the changes of the function and the acetylated homeostasis of the central cholinergic circuits of mice also were detected by molecular biology and pathology.
Results ICA can reduce the escape latency and searching distance of the mice with PSCI and this effect has dose-dependent.ICA can increase ACh levels and the ChAT mRNA and protein of expression levels in the central cholinergic circuits of the mice with PSCI, and this effect has dose-dependent. ICA can increase the expression levels of Ac-H3in the central cholinergic circuits of the mice with PSCI, and this effect has dose-dependent. But after the administration of the various doses of ICA, the expression level of Ac-H4did not change in any of the groups. ICA can improve the decline of the phosphorylated CREB in cholinergic circuits of mice with PSCI.
Conclusion (1) Transient MCAO caused cognitive dysfunction of mice which is associated with the decreased levels of ACh and CHAT in the central cholinergic circuits;
(2) The histone acetylation homeostasis of the central cholinergic circuits were impaired in post-stroke impairment model. At the same time, the levels of p-CREB in the corresponding brain regions were declined accordingly;
(3) ICA improved cognitive function of mice with PSCI, enhanced the levels of ACh and ChAT in the central cholinergic circuits and improved the damage of acetylated homeostasis. All these were related to the role of ICA that reversed this decline of the CREB phosphorylation.
引文
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