DL-3-正丁基邻苯二甲酸对血管性痴呆小鼠认知功能的影响及Nrf2/SIRT3信号通路的调节作用

中华行为医学与脑科学杂志 Pub Date : 2020-03-20 DOI:10.3760/CMA.J.CN371468-20190806-00527

Liwei Gao, Qiang Zhang, M. Li, Yanhong Dong

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Both the model group and the treatment group were repeated.The bilateral common carotid arteries were ligated three times to establish a mouse model of cognitive dysfunction caused by cerebral ischemia-reperfusion.The sham group only isolated the bilateral common carotid arteries and threaded the wires, but did not block blood flow.Morris water maze experiment was used to analyze the cognitive function of mice.HE staining was used to observe the changes of neuron morphology and structure in CA1 region of hippocampus, and immunohistochemical analysis was used to analyze the positive expression of caspase 3 and caspase 9 in mouse CA1 region of hippocampus.Western blot was used to detect mouse hippocampus Nrf2, p62, LC3, SIRT3 protein expression. \n \n \nResults \n(1) In Morris water maze experiment: compared with VD group, the escape latency of Sham group and Nrf2+ /+ NBP group was significantly shorter on the 5th day ((20.69±8.91) s, (7.58±9.47)s, (8.41±12.20)s; q=3.58, 5.07, both P 0.05). (2) Pathological results showed that, compared with VD group, the damage of pyramidal neurons in CA1 area of hippocampus in Sham group and Nrf2+ /+ NBP group was lighter, and that in Nrf2-/- VD group was more serious, and the improvement of neuron morphology was not obvious after NBP treatment.(3) The expression of apoptosis: compared with VD group, the expression of caspase-3 and caspase-9 in the CA1 area of hippocampus in Sham group and Nrf2+ /+ NBP group were significantly lower, and those in Nrf2-/-VD group were significantly higher (t=3.48, 2.95, 3.46, 2.93, -2.99, -3.77, all P 0.05). (4) Expression of related proteins: compared with VD group, Nrf2, SIRT3, p62 protein expression increased, LC3II/I ratio decreased in Nrf2+ /+ NBP group(t=-3.24, -4.04, -4.03, 3.62, all P<0.01); Nrf2, LC3II/ I ratio decreased, SIRT3, p62 protein expression increased in Sham group(t=3.44, 4.72, -3.52, -4.19, all P<0.01); Nrf2, SIRT3, p62 protein expression decreased and LC3II/I ratio increased in Nrf2-/-VD group(t=9.14, 4.20, 4.30, -3.78, all P<0.01); Compared with Nrf2-/- NBP, the expression of Nrf2, SIRT3, p62 decreased, and LC3II/I ratio increased in Nrf2-/-VD group(t=2.40, 3.24, 1.21, -1.16, all P<0.01). The expression of Nrf2, SIRT3, p62 protein in Nrf2+ /+ NBP group increased, and the ratio of LC3II/ I decreased (t=-3.29, -5.00, 6.24, all P<0.01). \n \n \nConclusion \nButylphthalide can reduce the apoptotic damage in hippocampus of VD mice and improve cognitive dysfunction caused by repeated ischemia-reperfusion injury.Regulating Nrf2 / SIRT3 pathway to inhibit hippocampal neuronal apoptosis and autophagy may be its role mechanism. \n \n \nKey words: \nButylphthalide(NBP); Vascular dementia; Nrf2; SIRT3; Apoptosis autophagy","PeriodicalId":9940,"journal":{"name":"中华行为医学与脑科学杂志","volume":"29 1","pages":"200-206"},"PeriodicalIF":0.0000,"publicationDate":"2020-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Effect of DL-3-n-butylphthalide on cognitive function and the regulating role of Nrf2/SIRT3 signaling pathway in vascular dementia mice\",\"authors\":\"Liwei Gao, Qiang Zhang, M. 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(2) Pathological results showed that, compared with VD group, the damage of pyramidal neurons in CA1 area of hippocampus in Sham group and Nrf2+ /+ NBP group was lighter, and that in Nrf2-/- VD group was more serious, and the improvement of neuron morphology was not obvious after NBP treatment.(3) The expression of apoptosis: compared with VD group, the expression of caspase-3 and caspase-9 in the CA1 area of hippocampus in Sham group and Nrf2+ /+ NBP group were significantly lower, and those in Nrf2-/-VD group were significantly higher (t=3.48, 2.95, 3.46, 2.93, -2.99, -3.77, all P 0.05). (4) Expression of related proteins: compared with VD group, Nrf2, SIRT3, p62 protein expression increased, LC3II/I ratio decreased in Nrf2+ /+ NBP group(t=-3.24, -4.04, -4.03, 3.62, all P<0.01); Nrf2, LC3II/ I ratio decreased, SIRT3, p62 protein expression increased in Sham group(t=3.44, 4.72, -3.52, -4.19, all P<0.01); Nrf2, SIRT3, p62 protein expression decreased and LC3II/I ratio increased in Nrf2-/-VD group(t=9.14, 4.20, 4.30, -3.78, all P<0.01); Compared with Nrf2-/- NBP, the expression of Nrf2, SIRT3, p62 decreased, and LC3II/I ratio increased in Nrf2-/-VD group(t=2.40, 3.24, 1.21, -1.16, all P<0.01). 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引用次数: 0

摘要

目的探讨丁基邻苯二甲酸酯（NBP）对血管性痴呆（VD）小鼠认知功能及Nrf2/SIRT3信号通路的影响。方法将野生型小鼠（Nrf2+/+）分为假手术组、模型组（VD组）、丁基邻苯二甲酸酯治疗组（Nrf2+/+NBP组），将Nrf2基因敲除小鼠（Nrf2-/-）分为Nrf2-/-模型组（Nrf2-/-VD组）和Nrf2--/-治疗组（Nrf2-/-NBP组）。模型组和治疗组均重复。结扎双侧颈总动脉三次，建立脑缺血再灌注引起认知功能障碍的小鼠模型。假手术组仅分离双侧颈总血管并穿线，但不阻断血流。采用Morris水迷宫实验对小鼠的认知功能进行分析。HE染色观察海马CA1区神经元形态结构的变化，免疫组化分析小鼠海马CA1区域caspase 3和caspase 9的阳性表达。免疫印迹法检测小鼠海马Nrf2、p62、LC3、SIRT3蛋白的表达。结果（1）Morris水迷宫实验：与VD组相比，Sham组和Nrf2+/+NBP组在第5天的逃生潜伏期显著缩短（（20.69±8.91）s、（7.58±9.47）s、和（8.41±12.20）s；q=3.58，5.07，均P＜0.05）。（2）病理结果显示，Sham组和Nrf2+/+NBP组海马CA1区锥体神经元损伤较VD组轻，Nrf2-/-VD组更严重，NBP治疗后神经元形态改善不明显。（3）凋亡的表达：与VD组相比，Sham组和Nrf2+/+NBP组海马CA1区胱天蛋白酶-3和胱天蛋白酶-9的表达显著降低，Nrf2-/-VD组的表达显著升高（t=3.48、2.95、3.46、2.93、-2.99、-3.77，均P 0.05），Nrf2+/+NBP组p62蛋白表达增加，LC3II/I比值降低（t=-3.24，-4.04，-4.03，3.62，均P<0.01）；Sham组Nrf2、LC3II/I比值降低，SIRT3、p62蛋白表达增加（t=3.44、4.72、-3.52、-4.19，均P<0.01）；Nrf2-/-VD组Nrf2、SIRT3、p62蛋白表达下降，LC3II/I比值升高（t=9.14,4.20,4.30,3.78，均P<0.01）；与Nrf2-/-NBP相比，Nrf2-+/-VD组Nrf2、SIRT3、p62蛋白表达下降，LC3II/I比值升高（t=2.40、3.24、1.21、-1.16，均P<0.01），结论丁基邻苯二甲酰胺能减轻VD小鼠海马细胞凋亡损伤，改善反复缺血再灌注损伤引起的认知功能障碍。调节Nrf2/SIRT3通路抑制海马神经元凋亡和自噬可能是其作用机制。关键词：丁基邻苯二甲酸酯；血管性痴呆；Nrf2；SIRT3；细胞凋亡自噬

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Effect of DL-3-n-butylphthalide on cognitive function and the regulating role of Nrf2/SIRT3 signaling pathway in vascular dementia mice

Objective To investigate the effects of butylphthalide(NBP) on cognitive function and Nrf2 / SIRT3 signal pathway in vascular dementia (VD) mice. Methods Wild-type mice (Nrf2+ /+ ) were divided into sham group, model group (VD group), butylphthalide treatment group (Nrf2+ /+ NBP group), and Nrf2 gene knockout mice (Nrf2-/-) were divided into Nrf2-/-model group (Nrf2-/-VD group) and Nrf2-/-treatment group (Nrf2-/-NBP group). Both the model group and the treatment group were repeated.The bilateral common carotid arteries were ligated three times to establish a mouse model of cognitive dysfunction caused by cerebral ischemia-reperfusion.The sham group only isolated the bilateral common carotid arteries and threaded the wires, but did not block blood flow.Morris water maze experiment was used to analyze the cognitive function of mice.HE staining was used to observe the changes of neuron morphology and structure in CA1 region of hippocampus, and immunohistochemical analysis was used to analyze the positive expression of caspase 3 and caspase 9 in mouse CA1 region of hippocampus.Western blot was used to detect mouse hippocampus Nrf2, p62, LC3, SIRT3 protein expression. Results (1) In Morris water maze experiment: compared with VD group, the escape latency of Sham group and Nrf2+ /+ NBP group was significantly shorter on the 5th day ((20.69±8.91) s, (7.58±9.47)s, (8.41±12.20)s; q=3.58, 5.07, both P 0.05). (2) Pathological results showed that, compared with VD group, the damage of pyramidal neurons in CA1 area of hippocampus in Sham group and Nrf2+ /+ NBP group was lighter, and that in Nrf2-/- VD group was more serious, and the improvement of neuron morphology was not obvious after NBP treatment.(3) The expression of apoptosis: compared with VD group, the expression of caspase-3 and caspase-9 in the CA1 area of hippocampus in Sham group and Nrf2+ /+ NBP group were significantly lower, and those in Nrf2-/-VD group were significantly higher (t=3.48, 2.95, 3.46, 2.93, -2.99, -3.77, all P 0.05). (4) Expression of related proteins: compared with VD group, Nrf2, SIRT3, p62 protein expression increased, LC3II/I ratio decreased in Nrf2+ /+ NBP group(t=-3.24, -4.04, -4.03, 3.62, all P<0.01); Nrf2, LC3II/ I ratio decreased, SIRT3, p62 protein expression increased in Sham group(t=3.44, 4.72, -3.52, -4.19, all P<0.01); Nrf2, SIRT3, p62 protein expression decreased and LC3II/I ratio increased in Nrf2-/-VD group(t=9.14, 4.20, 4.30, -3.78, all P<0.01); Compared with Nrf2-/- NBP, the expression of Nrf2, SIRT3, p62 decreased, and LC3II/I ratio increased in Nrf2-/-VD group(t=2.40, 3.24, 1.21, -1.16, all P<0.01). The expression of Nrf2, SIRT3, p62 protein in Nrf2+ /+ NBP group increased, and the ratio of LC3II/ I decreased (t=-3.29, -5.00, 6.24, all P<0.01). Conclusion Butylphthalide can reduce the apoptotic damage in hippocampus of VD mice and improve cognitive dysfunction caused by repeated ischemia-reperfusion injury.Regulating Nrf2 / SIRT3 pathway to inhibit hippocampal neuronal apoptosis and autophagy may be its role mechanism. Key words: Butylphthalide(NBP); Vascular dementia; Nrf2; SIRT3; Apoptosis autophagy

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中华行为医学与脑科学杂志

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期刊介绍： "Chinese Journal of Behavioral Medicine and Brain Science" (CN 37-1468/R, ISSN 1674-6554) is a national academic journal under the supervision of the National Health Commission, sponsored by the Chinese Medical Association and Jining Medical College. The journal was founded in June 1992 and was formerly known as "Chinese Journal of Behavioral Medicine" (1992-1993) and "Chinese Behavioral Medical Science" (1994-2008). In 2009, it was renamed "Chinese Journal of Behavioral Medicine and Brain Science" with the approval of the State Administration of Press, Publication, Radio, Film and Television. The purpose of "Chinese Journal of Behavioral Medicine and Brain Science" is to implement the health and health policies of the Party and the State, implement the principle of combining theory with practice and popularization and improvement, and reflect the major progress in the theory and practical application of behavioral medicine and brain science in my country. It publishes academic papers and scientific research results in the field of behavioral medicine and brain science in my country, and has columns such as monographs/reviews, basic research, clinical research, health prevention, methods and techniques, psychological behavior and evaluation, and systematic evaluation.