首乌益智胶囊对血管性认知障碍大鼠Notch信号通路相关基因及星形胶质细胞的作用研究
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摘要
目的:血管性认知障碍(VCI)近年来发病率和死亡率逐渐攀升,已成为全社会重要的公共卫生问题。神经元与星形胶质细胞之间的相互作用,是缺血性脑损伤后神经元能否存活的关键因素。本研究以Notch信号通路和星形胶质细胞为切入点,通过首乌益智胶囊治疗前后细胞变化及基因表达水平的改变,探讨其作用机制。为首乌益智胶囊治疗VCI从细胞水平和基因调控方面提供实验数据和理论依据。
方法:将SD大鼠通过线栓法制备大脑中动脉局灶脑缺血/再灌注VCI模型,经Morris水迷宫实验筛选出80只大鼠,随机分为假手术组、模型组、脑复康组、首乌益智胶囊组,每组20只。造模后药物干预4周。Morris水迷宫实验检测各组大鼠行为学改变;尼氏染色观察海马CA1区神经细胞形态学改变;透射电镜观察海马CA1区神经元超微结构病理学变化;免疫组织化学法检测海马CA1区GFAP、NGF的表达;实时荧光定量PCR检测Notch信号通路相关基因Notch1、PS1、Hes3、STAT3、GFAP、β-APP的表达。
结果:水迷宫结果表明,首乌益智胶囊组大鼠的定位航行和空间探索实验测试成绩明显优于模型组和脑复康组(P<0.01)。与模型组和脑复康组比较,首乌益智胶囊组海马锥体细胞排列较整齐、密集,胞浆中Nissl体较丰富;电镜观察细胞器结构基本正常。首乌益智胶囊组海马CA1区GFAP、NGF的表达较模型组和脑复康组显著升高(P<0.01)。与模型组比较,首乌益智胶囊组大鼠脑组织Notch1、Hes3、Stat3基因的表达,显著升高(P<0.01);与脑复康组比较,亦有明显升高(P<0.05)。首乌益智胶囊组GFAP基因的表达较模型组和脑复康组显著升高(P<0.01)。首乌益智胶囊组PS1基因的表达较模型组显著降低(P<0.01),较脑复康组亦有明显降低(P<0.05)。首乌益智胶囊组β-APP基因的表达较模型组明显降低(P <0.05);较脑复康组降低,无统计学意义(P >0.05)。
结论:1.首乌益智胶囊能保护神经元,减轻脑缺血对神经元的损伤,维持神经细胞结构与功能的完整。2.首乌益智胶囊能提高Notch信号通路Notch1、Stat3、Hes3、GFAP基因的表达,促进神经干细胞向星形胶质细胞分化、增殖;促进神经生长因子(NGF)的合成与分泌,对受损神经元产生保护、营养、修复和再生作用。3.首乌益智胶囊能降低PS1、β-APP基因的表达,使Aβ生成减少,减轻Aβ神经毒性,改善学习记忆能力。4.首乌益智胶囊能显著提高VCI大鼠的学习和记忆能力,是治疗VCI的有效方药,整体疗效优于脑复康。
Objective: The morbidity and mortality of Vascular cognitive impairment (VCI) has been higher and higher in recent years. It has become an important common sanitation problem.The interaction between Neurons and Astrocytes is the key factor of the neuron survival during cerebral ischemic injury. In this study, we explored the effects of ShouWuYiZhi capsule on astrocytes and investigated the mechanism of genes expression in Notch signaling pathway,and therefore provides the experimental data and theoretical base for the treatment from the cellular level and gene regulation of ShouWuYiZhi Capsule for vascular cognitive impairment.
Methods: Sprague-Dawley rats were used for VCI model establishment. 80 rats were screened after Morris water maze test and randomly divided into 4 groups: sham operation group, model group, piracetam group and Shouwuyizhi Capsule group, and each group has 20 rats. After 4-week administration, behavioral change of rat was recorded by Morris water maze. Histomorphological changes of neuron in hippocampal CA1 region were analysed after Nissl staining and ultrastructure alternation was observed via transmission electric microscope. GFAP and NGF expression were measured by immunohistochemistry and the expression of the genes of Notch1, PS1, Hes3, Stat3, GFAP,β-APP were measured using real time PCR.
Results: The results of Morris water maze showed that assessment of orientation test and spatial probe test from ShouWuYiZhi Capsule group were significantly higher than model group and Piracetam group (P <0.01).Compared with model group and Piracetam group, Neuron in the hippocampus cone of Shouwuyizhi Capsule group was more orderliness and confertim, and Nissl bodies were richer in cytoplasm. No obvious ultrastructure change of organelles was observed in ShouWuYiZhi Capsule group compared with sham operation group.Expression of GFAP and NGF was higher in ShouWuYiZhi Capsule group than in model group or Piracetam group (P<0.01).Expression of Notch1、Hes3、Stat3 and PS1 in ShouWuYiZhi Capsule group were increased significantly(V.S. model group P<0.01, V.S. Piracetam group P<0.05, respectively). Compared with model group and Piracetam group, the expression of GFAP gene was enhanced significantly(P<0.01). Compared with model group, the expression ofβ-APP gene of Shouwuyizhi Capsule group was decreased significantly(P<0.05), while no difference was showed compared with Piracetam group.
Conclusion: 1) ShouWuYiZhi capsule could Protect neurons against cerebral ischemic injury, and maintain the integrity of neurons’structure and function. 2) Mechanism of neuroprotection of ShouWuYiZhi capsule might be involved in the promotion of Notch1, Hes3, Stat3, and GFAP expression and the induction of differentiation neural stem cells to astrocytes and the production of NGF as well as the reduction of apoptotic neurons in VCI model, which might be the main factor contribute to neuron protection, neurotrophy, renovation and regeneration. 3)ShouWuYiZhi capsule could reduce the impairment of Aβagainst nerve cell and ameliorate the learning and memory capability due to decreasing the expression of PS1 andβ-APP. 4) ShouWuYiZhi capsule could improve the learning and memory ability of VCI model rats, and ShouWuYiZhi capsule is a valid therapy to VCI,which might be more effective than piracetam.
方法:将SD大鼠通过线栓法制备大脑中动脉局灶脑缺血/再灌注VCI模型,经Morris水迷宫实验筛选出80只大鼠,随机分为假手术组、模型组、脑复康组、首乌益智胶囊组,每组20只。造模后药物干预4周。Morris水迷宫实验检测各组大鼠行为学改变;尼氏染色观察海马CA1区神经细胞形态学改变;透射电镜观察海马CA1区神经元超微结构病理学变化;免疫组织化学法检测海马CA1区GFAP、NGF的表达;实时荧光定量PCR检测Notch信号通路相关基因Notch1、PS1、Hes3、STAT3、GFAP、β-APP的表达。
结果:水迷宫结果表明,首乌益智胶囊组大鼠的定位航行和空间探索实验测试成绩明显优于模型组和脑复康组(P<0.01)。与模型组和脑复康组比较,首乌益智胶囊组海马锥体细胞排列较整齐、密集,胞浆中Nissl体较丰富;电镜观察细胞器结构基本正常。首乌益智胶囊组海马CA1区GFAP、NGF的表达较模型组和脑复康组显著升高(P<0.01)。与模型组比较,首乌益智胶囊组大鼠脑组织Notch1、Hes3、Stat3基因的表达,显著升高(P<0.01);与脑复康组比较,亦有明显升高(P<0.05)。首乌益智胶囊组GFAP基因的表达较模型组和脑复康组显著升高(P<0.01)。首乌益智胶囊组PS1基因的表达较模型组显著降低(P<0.01),较脑复康组亦有明显降低(P<0.05)。首乌益智胶囊组β-APP基因的表达较模型组明显降低(P <0.05);较脑复康组降低,无统计学意义(P >0.05)。
结论:1.首乌益智胶囊能保护神经元,减轻脑缺血对神经元的损伤,维持神经细胞结构与功能的完整。2.首乌益智胶囊能提高Notch信号通路Notch1、Stat3、Hes3、GFAP基因的表达,促进神经干细胞向星形胶质细胞分化、增殖;促进神经生长因子(NGF)的合成与分泌,对受损神经元产生保护、营养、修复和再生作用。3.首乌益智胶囊能降低PS1、β-APP基因的表达,使Aβ生成减少,减轻Aβ神经毒性,改善学习记忆能力。4.首乌益智胶囊能显著提高VCI大鼠的学习和记忆能力,是治疗VCI的有效方药,整体疗效优于脑复康。
Objective: The morbidity and mortality of Vascular cognitive impairment (VCI) has been higher and higher in recent years. It has become an important common sanitation problem.The interaction between Neurons and Astrocytes is the key factor of the neuron survival during cerebral ischemic injury. In this study, we explored the effects of ShouWuYiZhi capsule on astrocytes and investigated the mechanism of genes expression in Notch signaling pathway,and therefore provides the experimental data and theoretical base for the treatment from the cellular level and gene regulation of ShouWuYiZhi Capsule for vascular cognitive impairment.
Methods: Sprague-Dawley rats were used for VCI model establishment. 80 rats were screened after Morris water maze test and randomly divided into 4 groups: sham operation group, model group, piracetam group and Shouwuyizhi Capsule group, and each group has 20 rats. After 4-week administration, behavioral change of rat was recorded by Morris water maze. Histomorphological changes of neuron in hippocampal CA1 region were analysed after Nissl staining and ultrastructure alternation was observed via transmission electric microscope. GFAP and NGF expression were measured by immunohistochemistry and the expression of the genes of Notch1, PS1, Hes3, Stat3, GFAP,β-APP were measured using real time PCR.
Results: The results of Morris water maze showed that assessment of orientation test and spatial probe test from ShouWuYiZhi Capsule group were significantly higher than model group and Piracetam group (P <0.01).Compared with model group and Piracetam group, Neuron in the hippocampus cone of Shouwuyizhi Capsule group was more orderliness and confertim, and Nissl bodies were richer in cytoplasm. No obvious ultrastructure change of organelles was observed in ShouWuYiZhi Capsule group compared with sham operation group.Expression of GFAP and NGF was higher in ShouWuYiZhi Capsule group than in model group or Piracetam group (P<0.01).Expression of Notch1、Hes3、Stat3 and PS1 in ShouWuYiZhi Capsule group were increased significantly(V.S. model group P<0.01, V.S. Piracetam group P<0.05, respectively). Compared with model group and Piracetam group, the expression of GFAP gene was enhanced significantly(P<0.01). Compared with model group, the expression ofβ-APP gene of Shouwuyizhi Capsule group was decreased significantly(P<0.05), while no difference was showed compared with Piracetam group.
Conclusion: 1) ShouWuYiZhi capsule could Protect neurons against cerebral ischemic injury, and maintain the integrity of neurons’structure and function. 2) Mechanism of neuroprotection of ShouWuYiZhi capsule might be involved in the promotion of Notch1, Hes3, Stat3, and GFAP expression and the induction of differentiation neural stem cells to astrocytes and the production of NGF as well as the reduction of apoptotic neurons in VCI model, which might be the main factor contribute to neuron protection, neurotrophy, renovation and regeneration. 3)ShouWuYiZhi capsule could reduce the impairment of Aβagainst nerve cell and ameliorate the learning and memory capability due to decreasing the expression of PS1 andβ-APP. 4) ShouWuYiZhi capsule could improve the learning and memory ability of VCI model rats, and ShouWuYiZhi capsule is a valid therapy to VCI,which might be more effective than piracetam.
引文
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