川陈皮素对糖尿病认知功能障碍大鼠神经细胞损伤改善的实验研究
|
摘要
目的探讨川陈皮素对糖尿病大鼠认知功能的改善及作用机制。方法选取12周龄SD大鼠40只,随机分为正常对照组,糖尿病模型组,α-硫辛酸组,高、中、低剂量川陈皮素组,每组至少6只动物,采用腹腔注射1%链脲佐菌素(STZ)溶液建立糖尿病大鼠模型,其中低剂量组、中剂量组和高剂量组分别按照10、20和30 mg/kg给予川陈皮素,α-硫辛酸组给予60 mg/kgα-硫辛酸,每日1次,连续8周,于大鼠22周龄时行Morris水迷宫试验,采用电子显微镜观察海马组织,western blot检测海马组织Nrf2、HO-1蛋白表达。结果高剂量组逃避潜伏期分别为(16.62±1.99)s,明显低于糖尿病模型组、低剂量组和中剂量组(P<0.05),与α-硫辛酸组比较差异无统计学意义(P>0.05),但仍高于正常对照组(P<0.05);高剂量组穿越目标区次数分别为(7.11±1.12)次,明显高于糖尿病模型组、低剂量组和中剂量组(P<0.05),与α-硫辛酸组比较差异无统计学意义(P>0.05),但仍低于正常对照组(P<0.05);低剂量组、中剂量组、高剂量组和-硫辛酸组大鼠海马神经元细胞结构较糖尿病模型组有所改善,其中高剂量组和α-硫辛酸组形态结构接近正常对照组;高剂量组海马组织Nrf2和HO-1蛋白相对表达量分别为(0.812±0.113)和(0.877±0.117),明显高于糖尿病模型组、低剂量组和中剂量组(P<0.05),与α-硫辛酸组比较差异无统计学意义(P>0.05),仍低于正常对照组(P<0.05)。结论川陈皮素能有效改善糖尿病大鼠认知功能以及海马组织神经元结构,上调Nrf2和HO-1表达。
Objective The aim of this study was to investigate the cognitive function improvement and mechanism of nobiletin in diabetic rats. Methods 40 Sprague-Dawley rats of 12 weeks old were randomly divided into normal control group(n=8),diabetes model group(n=8), α-lipoic acid group(n=6), low dose group(n=6), middle dose group(n=6) and high dose group(n =6). Diabetic rats were induced by intraperitoneal injection of 1% STZ solution. Low dose group, middle dose group and high dose group were given 10, 20 and 30 mg/kg nobiletin respectively. 60 mg/kg α-lipoic acid was given to the α-lipoic acid group, 1 times a day for 8 weeks. The Morris water maze test was performed at the age of 22 weeks, the hippocampal formation was observed by electron microscope, and the expression of Nrf2 and HO-1 protein in hippocampus was detected by Western blot. Results The escape latency period of high dose group(16.62±1.99) were significantly lower than that of the diabetic model group, low dose group and middle dose group(P<0.05), with no significant difference compared with the α-lipoic acid group(P>0.05). However, it was still higher than the normal control group(P<0.05). The number of crossing the target area in high dose group were(7.11±1.12) times, which were significantly higher than that of the diabetic model group,low dose group and middle dose group(P<0.05), with no significant difference compared with the α-lipoic acid group(P>0.05).However, it was still lower than that of the normal control group(P<0.05). The hippocampal neuron cell structure in the low dose group, the middle dose group, the high dose group and the diabetic rats were better than that of the diabetic model group. And the morphologic structure of the high dose group and the α-lipoic acid group were close to the normal control group. The relative expression of Nrf2 and HO-1 protein in the hippocampus of high dose group was(0.812±0.113) and(0.877±0.117), which were significantly higher than that in the diabetic model group, low dose group and middle dose group(P<0.05),was no significant difference compared with the α-lipoic acid group(P>0.05), and still lower than that of the normal control group(P <0.05). Conclusion Nobiletin can effectively improve the cognitive function of diabetic rats, and increase the expression of Nrf2 and HO-1 in hippocampal neurons.
Objective The aim of this study was to investigate the cognitive function improvement and mechanism of nobiletin in diabetic rats. Methods 40 Sprague-Dawley rats of 12 weeks old were randomly divided into normal control group(n=8),diabetes model group(n=8), α-lipoic acid group(n=6), low dose group(n=6), middle dose group(n=6) and high dose group(n =6). Diabetic rats were induced by intraperitoneal injection of 1% STZ solution. Low dose group, middle dose group and high dose group were given 10, 20 and 30 mg/kg nobiletin respectively. 60 mg/kg α-lipoic acid was given to the α-lipoic acid group, 1 times a day for 8 weeks. The Morris water maze test was performed at the age of 22 weeks, the hippocampal formation was observed by electron microscope, and the expression of Nrf2 and HO-1 protein in hippocampus was detected by Western blot. Results The escape latency period of high dose group(16.62±1.99) were significantly lower than that of the diabetic model group, low dose group and middle dose group(P<0.05), with no significant difference compared with the α-lipoic acid group(P>0.05). However, it was still higher than the normal control group(P<0.05). The number of crossing the target area in high dose group were(7.11±1.12) times, which were significantly higher than that of the diabetic model group,low dose group and middle dose group(P<0.05), with no significant difference compared with the α-lipoic acid group(P>0.05).However, it was still lower than that of the normal control group(P<0.05). The hippocampal neuron cell structure in the low dose group, the middle dose group, the high dose group and the diabetic rats were better than that of the diabetic model group. And the morphologic structure of the high dose group and the α-lipoic acid group were close to the normal control group. The relative expression of Nrf2 and HO-1 protein in the hippocampus of high dose group was(0.812±0.113) and(0.877±0.117), which were significantly higher than that in the diabetic model group, low dose group and middle dose group(P<0.05),was no significant difference compared with the α-lipoic acid group(P>0.05), and still lower than that of the normal control group(P <0.05). Conclusion Nobiletin can effectively improve the cognitive function of diabetic rats, and increase the expression of Nrf2 and HO-1 in hippocampal neurons.
引文
[1]刘贵春,江朝秀,彭镌宝,等.腹腔注射丙酮酸乙酯脑缺血再灌注大鼠认知功能、海马Nrf2基因表达及神经细胞线粒体形态变化[J].山东医药,2016,56(43):38-40.
[2]Zhao W,Huang X,Zhang L,et al.Penehyclidine hydrochloride pretreatment ameliorates rhabdomyolysis-induced AKI by activating the Nrf2/HO-1 pathway and alleviating[corrected]endoplasmic reticulum stress in rats[J].PLOS One,2016,11(3):e0151158.
[3]Furfaro AL,Piras S,Domenicotti C,et al.Role of Nrf2,HO-1 and GSH in neuroblastoma cell resistance to bortezomib[J].PLOS One,2016,11(3):e0152465.
[4]黄娟,廖君,彭熙炜,等.脑泰方对脑缺血/再灌注大鼠海马区Nrf2、HO-1和膜铁转运辅助蛋白表达的影响[J].中国药理学通报,2017,33(10):1467-1472.
[5]张红蕊,赵轶群,高晓红,等.川陈皮素对糖尿病大鼠海马Nrf-2表达及认知功能的影响[J].重庆医学,2017,46(6):732-734.
[6]田敏,张思远,韩佩晏,等.叔丁基对苯二酚激活Nrf2信号通路增强对2型糖尿病大鼠视网膜的保护作用[J].眼科新进展,2017,37(3):220-224.
[7]Zhang L,Zhang X,Zhang C,et al.Nobiletin promotes antioxidant and anti-inflammatory responses and elicits protection against ischemic stroke in vivo[J].Brain Research,2016,1636:130-141.
[8]孙伟娜,王镁.中药复方糖肾安对实验性2型糖尿病大鼠肾脏ROS水平及Nrf2、HO-1表达的影响[J].吉林中医药,2016,36(12):1247-1250.
[9]高梦颖,何永昌,孙国柱,等.大鼠液压冲击脑损伤Nrf2、HO-1和NQO-1动态表达变化及意义[J].第三军医大学学报,2016,38(18):2023-2028.
[10]Hill JM,Lukiw WJ.micro RNA(mi RNA)-Mediated pathogenetic signaling in alzheimer's disease(AD)[J].Neurochemical Research,2016,41(1/2,SI):96-100.
[11]Liao GX,Li R,Chen XH,et al.Sodium valproate prevents radiation-induced injury in hippocampal neurons via activation of the Nrf2/HO-1 pathway[J].Neuroscience,2016,331:40-51.
[12]傅晓燕,雷珊珊,李雄英.黄芪配方颗粒对衰老大鼠认知功能的影响及机制初探[J].中药材,2017,40(5):1184-1189.
[13]袁旭,刘新,郝旺青,等.川陈皮素微乳离子敏感型凝胶剂的研制及体外释放考察[J].中药材,2016,39(10):2290-2294.
[14]杨华,田萌,刘喜燕.川陈皮素对脑梗死大鼠HIF-1α和VEGF含量及神经细胞凋亡的影响与机制[J].临床和实验医学杂志,2017,16(20):1980-1983.
[15]白洁,赵晟宇,范小庆,等.川陈皮素对P-糖蛋白的体内外抑制作用及分子机制研究[J].药学学报,2018,53(5):754-759.
[2]Zhao W,Huang X,Zhang L,et al.Penehyclidine hydrochloride pretreatment ameliorates rhabdomyolysis-induced AKI by activating the Nrf2/HO-1 pathway and alleviating[corrected]endoplasmic reticulum stress in rats[J].PLOS One,2016,11(3):e0151158.
[3]Furfaro AL,Piras S,Domenicotti C,et al.Role of Nrf2,HO-1 and GSH in neuroblastoma cell resistance to bortezomib[J].PLOS One,2016,11(3):e0152465.
[4]黄娟,廖君,彭熙炜,等.脑泰方对脑缺血/再灌注大鼠海马区Nrf2、HO-1和膜铁转运辅助蛋白表达的影响[J].中国药理学通报,2017,33(10):1467-1472.
[5]张红蕊,赵轶群,高晓红,等.川陈皮素对糖尿病大鼠海马Nrf-2表达及认知功能的影响[J].重庆医学,2017,46(6):732-734.
[6]田敏,张思远,韩佩晏,等.叔丁基对苯二酚激活Nrf2信号通路增强对2型糖尿病大鼠视网膜的保护作用[J].眼科新进展,2017,37(3):220-224.
[7]Zhang L,Zhang X,Zhang C,et al.Nobiletin promotes antioxidant and anti-inflammatory responses and elicits protection against ischemic stroke in vivo[J].Brain Research,2016,1636:130-141.
[8]孙伟娜,王镁.中药复方糖肾安对实验性2型糖尿病大鼠肾脏ROS水平及Nrf2、HO-1表达的影响[J].吉林中医药,2016,36(12):1247-1250.
[9]高梦颖,何永昌,孙国柱,等.大鼠液压冲击脑损伤Nrf2、HO-1和NQO-1动态表达变化及意义[J].第三军医大学学报,2016,38(18):2023-2028.
[10]Hill JM,Lukiw WJ.micro RNA(mi RNA)-Mediated pathogenetic signaling in alzheimer's disease(AD)[J].Neurochemical Research,2016,41(1/2,SI):96-100.
[11]Liao GX,Li R,Chen XH,et al.Sodium valproate prevents radiation-induced injury in hippocampal neurons via activation of the Nrf2/HO-1 pathway[J].Neuroscience,2016,331:40-51.
[12]傅晓燕,雷珊珊,李雄英.黄芪配方颗粒对衰老大鼠认知功能的影响及机制初探[J].中药材,2017,40(5):1184-1189.
[13]袁旭,刘新,郝旺青,等.川陈皮素微乳离子敏感型凝胶剂的研制及体外释放考察[J].中药材,2016,39(10):2290-2294.
[14]杨华,田萌,刘喜燕.川陈皮素对脑梗死大鼠HIF-1α和VEGF含量及神经细胞凋亡的影响与机制[J].临床和实验医学杂志,2017,16(20):1980-1983.
[15]白洁,赵晟宇,范小庆,等.川陈皮素对P-糖蛋白的体内外抑制作用及分子机制研究[J].药学学报,2018,53(5):754-759.