胰高血糖素样肽1对2型糖尿病合并阿尔茨海默病大鼠学习记忆功能的影响
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摘要
目的观察胰高血糖素样肽1(GLP-1)对2型糖尿病(T_2DM)合并阿尔茨海默病(AD)大鼠学习记忆功能的影响。方法 60只SD大鼠完全随机分为正常对照组、T_2DM组、AD组、T_2DM+AD组,各15只。T_2DM组、AD组和T_2DM+AD组分别制备T_2DM模型、AD模型和T_2DM+AD模型,模型制备成功后皮下注射GLP-1类似物利拉鲁肽注射液300μg/(kg·d),连用4周;正常对照组给予等体积0.9%氯化钠注射液皮下注射4周。比较干预前后大鼠体质量、空腹血糖及Morris水迷宫实验评价状况。结果干预前,与正常对照组比较,T_2DM组和T_2DM+AD组空腹血糖明显高,且T_2DM+AD组高于T_2DM组,差异均有统计学意义(均P <0. 05);干预后,T_2DM组和T_2DM+AD组空腹血糖较干预前明显下降,差异均有统计学意义(均P <0. 05)。干预前,与正常对照组比较,AD组和T_2DM+AD组逃避潜伏期明显延长[(105±12)、(114±14)s比(53±5)s],且T_2DM+AD组长于AD组,差异均有统计学意义(均P <0.05);干预后,AD组和T_2DM+AD组逃避潜伏期[(67±7)、(69±8)s]较干预前缩短,差异均有统计学意义(均P<0. 05)。干预前,与正常对照组比较,AD组和T_2DM+AD组第四象限游泳路程缩短,且T_2DM+AD组短于AD组,差异均有统计学意义(均P <0. 05);干预后,AD组和T_2DM+AD组第四象限游泳路程较干预前延长,差异均有统计学意义(均P <0. 05)。干预前,与正常对照组比较,AD组和T_2DM+AD组穿越平台次数减少,且T_2DM+AD组少于AD组,差异均有统计学意义(均P <0. 05);干预后,AD组和T_2DM+AD组穿越平台次数较干预前增多,差异均有统计学意义(均P<0.05)。结论 GLP-1对降低T_2DM鼠的血糖水平及改善AD鼠的学习记忆能力均有作用,在T_2DM合并AD的治疗领域可能有较大潜力。
Objective To observe the influence of glucagon-like peptide-1(GLP-1) on learning and memory abilities in type 2 diabetes mellitus(T_2 DM) and Alzheimer disease(AD) rats. Methods Sixty SD rats were randomly prepared for normal control group, T2 DM model group, AD model group and T2 DM + AD model group, with 15 rats in each group. After modeling, the rats were given GLP-1 analogue liraglutide by subcutaneous injection at the dose of 300 μg/(kg · d) for 4 weeks; the normal control group was given isometric subcutaneous injection of 0. 9% sodium chloride for 4 weeks. Body weight, fasting blood glucose level and results of Morris water maze test were analyzed. Results Before intervention, fasting blood glucose of rats in the T_2 DM group and T_2 DM + AD group were significantly higher than that in the normal control group; the level of blood glucose in the T_2 DM + AD group was significantly higher than that in the T_2 DM group(all P <0. 05). After intervention, fasting blood glucose in the T_2 DM group and T_2 DM + AD group were significantly lower than those before intervention(both P < 0. 05). Before intervention, escape latencies in the AD group and T_2 DM + AD group were significantly longer than that in the normal control group [(105 ±12),(114±14)s vs(53±5)s]; escape latencies in the T_2 DM + AD group was significantly longer than that in the AD group(all P < 0. 05). After intervention, escape latencies in the AD group and T_2 DM + AD group[(67 ±7),(69 ±8)s] were significantly shorter than those before intervention(both P <0. 05). Before intervention, the fourth quadrant swimming distances in the AD group and T_2 DM + AD group were significantly shorter than that in the normal control group; the fourth quadrant swimming distance in the T_2 DM + AD group was significantly shorter than that in the AD group(all P < 0. 05). After intervention, the fourth quadrant swimming distances in the AD group and T2 DM + AD group were significantly longer than those before intervention(both P < 0. 05). Before intervention, the numbers of platform crossings in the AD group and T_2 DM + AD group were significantly less than that in the normal control group; the number in the T_2 DM + AD group was less than that in the AD group(all P <0.05). After intervention, the numbers of platform crossings in the AD group and T_2 DM + AD group were significantly more than those before intervention(P <0.05). Conclusion GLP-1 can reduce blood glucose level of T_2 DM rats and improve learning and memory abilities of AD rats, it may have a great potential value in the treatment of T_2 DM combined with AD.
Objective To observe the influence of glucagon-like peptide-1(GLP-1) on learning and memory abilities in type 2 diabetes mellitus(T_2 DM) and Alzheimer disease(AD) rats. Methods Sixty SD rats were randomly prepared for normal control group, T2 DM model group, AD model group and T2 DM + AD model group, with 15 rats in each group. After modeling, the rats were given GLP-1 analogue liraglutide by subcutaneous injection at the dose of 300 μg/(kg · d) for 4 weeks; the normal control group was given isometric subcutaneous injection of 0. 9% sodium chloride for 4 weeks. Body weight, fasting blood glucose level and results of Morris water maze test were analyzed. Results Before intervention, fasting blood glucose of rats in the T_2 DM group and T_2 DM + AD group were significantly higher than that in the normal control group; the level of blood glucose in the T_2 DM + AD group was significantly higher than that in the T_2 DM group(all P <0. 05). After intervention, fasting blood glucose in the T_2 DM group and T_2 DM + AD group were significantly lower than those before intervention(both P < 0. 05). Before intervention, escape latencies in the AD group and T_2 DM + AD group were significantly longer than that in the normal control group [(105 ±12),(114±14)s vs(53±5)s]; escape latencies in the T_2 DM + AD group was significantly longer than that in the AD group(all P < 0. 05). After intervention, escape latencies in the AD group and T_2 DM + AD group[(67 ±7),(69 ±8)s] were significantly shorter than those before intervention(both P <0. 05). Before intervention, the fourth quadrant swimming distances in the AD group and T_2 DM + AD group were significantly shorter than that in the normal control group; the fourth quadrant swimming distance in the T_2 DM + AD group was significantly shorter than that in the AD group(all P < 0. 05). After intervention, the fourth quadrant swimming distances in the AD group and T2 DM + AD group were significantly longer than those before intervention(both P < 0. 05). Before intervention, the numbers of platform crossings in the AD group and T_2 DM + AD group were significantly less than that in the normal control group; the number in the T_2 DM + AD group was less than that in the AD group(all P <0.05). After intervention, the numbers of platform crossings in the AD group and T_2 DM + AD group were significantly more than those before intervention(P <0.05). Conclusion GLP-1 can reduce blood glucose level of T_2 DM rats and improve learning and memory abilities of AD rats, it may have a great potential value in the treatment of T_2 DM combined with AD.
引文
[1] Schilling MA. Unraveling Alzheimer's:making sense of the relationshipbetween diabetes and Alzheimer's disease[J]. J Alzheimers Dis,2016,51(4):961-977. DOI:10.3233/JAD-150980.
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[5]汤球.2型糖尿病大鼠模型的制备与评价[J].四川医学,2011,32(4):463-465. DOI:10.3969/j. issn. 1004-0501.2011.04.006.Tang Q. Preparation and evaluation of rat model of type 2 diabetes[J].Sichuan Medical Journal, 2011,32(4);463-465. DOI:10.3969/j. issn. 1004-0501.2011.04.006.
[6]徐海伟,黎海蒂,范晓棠,等.AD大鼠模型的制备及行为学和超微结构研究[J].中国行为医学科学,2003,12(2):123-124,127. DOI:10.3760/cma. j. issn. 1674-6554.2003.02.002.Xu HW, Li HD, Fan XT, et al. Establishment of Alzheimer disease rat model and its praxiology and ultrastructure research[J].Chinese Journal of Behavioral Medicine and Brain Science, 2003,12(2):123-124,127. DOI:10.3760/cma. j. issn. 1674-6554.2003.02.002.
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[8] Gaspari T, Liu H, Welungoda I, et al. A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/-mouse model[J]. Diab Vase Dis Res, 2011,8(2):117-124. DOI:10.1177/1479164111404257.
[9]彭璇,吴刚,吴昊,等.Morris水迷宫训练对老年痴呆大鼠模型学习记忆能力及海马组织肿瘤坏死因子-α、超氧化物歧化酶、丙二醛水平的影响[J].中国老年学杂志,2017,37(8):1833-1835. DOI:10. 3969/j. issn. 1005-9202.2017.08.005.Peng X, Wu G, Wu H, et al. Influence of Morris water maze training on Azheimer's disease rats learning and memory ability and the expressions of TNF-a,SOD and MDA in hippocampal tissue[J].Chinese Journal of Gerontology, 2017,37(8):1833-1835. DOI:10.3969/j. issn. 1005-9202.2017.08.005.
[10]周娇娇,阙建宇,于雯雯,等.Morris水迷宫检测动物学习记忆水平的方法学[J].中国老年学杂志,2017,37(24):6274-6277.DOI:10. 3969/j. issn. 1005-9202.2017.24. 116.Zhou JJ, Kan JY, Yu WW, et al. Morris water maze detection of learning and memory in animals[J]. Chinese Journal of Gerontology,2017,37(24):6274-6277. DOI:10. 3969/j. issn. 1005-9202. 2017.24.116.
[11]姜大景,胡婷婷,汪华,等.阿尔兹海默病的发生与常见血管危险因素的相关性研究[J].现代中西医结合杂志,2017,26(22):2422-2424,2428. DOI:10.3969/j. issn. 1008-8849.2017.22.009.Jiang DJ, Hu TT, Wang H, et al. Study on the correlation between the onset of Alzheimer's disease and vascular risk factor[J].Modem Journal of Integrated Traditional Chinese and Western Medicine, 2017,26(22):2422-2424,2428. DOI:10. 3969/j. issn.1008-8849.2017.22.009.
[12] Arnold SE, Arvanitakis Z, Macauley-Rambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease:concepts and conundrums[J]. Nat Rev Neurol, 2018,14(3):168-181. DOI:10. 1038/nrneurol.2017. 185.
[13] Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue:novel distribution revealed with extensively validated monoclonal antibody[J]. Endocrinology,2014,155(4):1280-1290. DOI:10.1210/en. 2013-1934.
[14] Li L, Zhang ZF, Holscher C, et al.(Val~8)Glucagon-like peptide-1 prevents tau hyperphosphorylation, impairment of spatial learning and ultra-structural cellular damage induced by streptozotocin in rat brains[J]. Eur J Pharmacol, 2012,674(2-3):280-286. DOI:10.1016/j.ejphar.2011.11.005.
[15] Chen S, Liu AR, An FM, et al. Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related Alzheimer's disease by exendin-4[J]. Age(Dordr), 2012,34(5):1211-1224.
[2] Bianchi VE, Locatelli V, Rizzi L. Neurotrophic and neuroregenerative effects of GH/IGF1[J]. Int J Mol Sci, 2017, 18(11):E2441. DOI:10. 3390/ijms18112441.
[3] Hansen HH, Fabricius K, Barkholt P, et al. Long-term treatment with liraglutide, a glucagon-like peptide-1(GLP-1)receptor agonist, has no effect onβ-amyloid plaque load in two transgenic APP/PS1 mouse models of Alzheimer's disease[J]. PLoS One,2016,11(7):e0158205. DOI:10.1371/journal. pone.0158205.
[4] Bae CS, Song J. The role of glucagon-like peptide 1(GLP1)in type 3 diabetes:GLP-1 controls insulin resistance, neuroinflammation and neurogenesis in the brain[J]. Int J Mol Sci, 2017,18(11):E2493. DOI:10.3390/ijms18112493.
[5]汤球.2型糖尿病大鼠模型的制备与评价[J].四川医学,2011,32(4):463-465. DOI:10.3969/j. issn. 1004-0501.2011.04.006.Tang Q. Preparation and evaluation of rat model of type 2 diabetes[J].Sichuan Medical Journal, 2011,32(4);463-465. DOI:10.3969/j. issn. 1004-0501.2011.04.006.
[6]徐海伟,黎海蒂,范晓棠,等.AD大鼠模型的制备及行为学和超微结构研究[J].中国行为医学科学,2003,12(2):123-124,127. DOI:10.3760/cma. j. issn. 1674-6554.2003.02.002.Xu HW, Li HD, Fan XT, et al. Establishment of Alzheimer disease rat model and its praxiology and ultrastructure research[J].Chinese Journal of Behavioral Medicine and Brain Science, 2003,12(2):123-124,127. DOI:10.3760/cma. j. issn. 1674-6554.2003.02.002.
[7] George P,Charles W.大鼠脑立体定位图谱[M]. 3版.北京:人民卫生出版社,2005:24-26.George P, Charles W. The rat brain in stereotaxic coordinates[M].3rd ed. Beijing:People's Health Publishing House, 2005:24-26.
[8] Gaspari T, Liu H, Welungoda I, et al. A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/-mouse model[J]. Diab Vase Dis Res, 2011,8(2):117-124. DOI:10.1177/1479164111404257.
[9]彭璇,吴刚,吴昊,等.Morris水迷宫训练对老年痴呆大鼠模型学习记忆能力及海马组织肿瘤坏死因子-α、超氧化物歧化酶、丙二醛水平的影响[J].中国老年学杂志,2017,37(8):1833-1835. DOI:10. 3969/j. issn. 1005-9202.2017.08.005.Peng X, Wu G, Wu H, et al. Influence of Morris water maze training on Azheimer's disease rats learning and memory ability and the expressions of TNF-a,SOD and MDA in hippocampal tissue[J].Chinese Journal of Gerontology, 2017,37(8):1833-1835. DOI:10.3969/j. issn. 1005-9202.2017.08.005.
[10]周娇娇,阙建宇,于雯雯,等.Morris水迷宫检测动物学习记忆水平的方法学[J].中国老年学杂志,2017,37(24):6274-6277.DOI:10. 3969/j. issn. 1005-9202.2017.24. 116.Zhou JJ, Kan JY, Yu WW, et al. Morris water maze detection of learning and memory in animals[J]. Chinese Journal of Gerontology,2017,37(24):6274-6277. DOI:10. 3969/j. issn. 1005-9202. 2017.24.116.
[11]姜大景,胡婷婷,汪华,等.阿尔兹海默病的发生与常见血管危险因素的相关性研究[J].现代中西医结合杂志,2017,26(22):2422-2424,2428. DOI:10.3969/j. issn. 1008-8849.2017.22.009.Jiang DJ, Hu TT, Wang H, et al. Study on the correlation between the onset of Alzheimer's disease and vascular risk factor[J].Modem Journal of Integrated Traditional Chinese and Western Medicine, 2017,26(22):2422-2424,2428. DOI:10. 3969/j. issn.1008-8849.2017.22.009.
[12] Arnold SE, Arvanitakis Z, Macauley-Rambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease:concepts and conundrums[J]. Nat Rev Neurol, 2018,14(3):168-181. DOI:10. 1038/nrneurol.2017. 185.
[13] Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue:novel distribution revealed with extensively validated monoclonal antibody[J]. Endocrinology,2014,155(4):1280-1290. DOI:10.1210/en. 2013-1934.
[14] Li L, Zhang ZF, Holscher C, et al.(Val~8)Glucagon-like peptide-1 prevents tau hyperphosphorylation, impairment of spatial learning and ultra-structural cellular damage induced by streptozotocin in rat brains[J]. Eur J Pharmacol, 2012,674(2-3):280-286. DOI:10.1016/j.ejphar.2011.11.005.
[15] Chen S, Liu AR, An FM, et al. Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related Alzheimer's disease by exendin-4[J]. Age(Dordr), 2012,34(5):1211-1224.