利拉鲁肽改善2型糖尿病大鼠空间学习和记忆能力机制的研究

Liraglutide improves the spatial learning and memory function in rats with type 2 diabetes mellitus

目的探讨利拉鲁肽对T2DM大鼠空间学习和记忆功能的影响及相关机制。方法SD大鼠随机分为对照组(NC,n=12)、T2DM组(n=10)及利拉鲁肽组(Lir,n=10)。Morris水迷宫法检测各组空间学习记忆能力,原位末端标记(TUNEL)法检测海马神经元凋亡,荧光定量PCR法检测TNF-α、IL-1β、IL-6 mRNA表达,Western blot法检测血红素加氧酶(HO-1)、NADPH氧化酶1(NOX1)、B淋巴细胞瘤-2(Bcl-2)和Bcl-2相关X蛋白(Bax)蛋白表达。结果Lir组在目标象限内停留时间比高于T2DM组(P<0.05)。Lir组第3~5天逃避潜伏期低于T2DM组(P<0.05)。Lir组海马神经元凋亡显著降低,染色质浓染、细胞核固缩现象减轻。与T2DM组比较,Lir组海马组织丙二醛降低,总抗氧化能力、超氧化物歧化酶、HO-1蛋白表达、Bcl-2蛋白表达升高(P<0.05),TNF-αmRNA、IL-1βmRNA、IL-6 mRNA、NOX1蛋白表达、Bax蛋白表达降低(P<0.05)。结论利拉鲁肽改善T2DM大鼠空间学习和记忆功能,作用机制可能与增强海马组织抗氧化抗炎能力,减少神经元凋亡相关。

Objective To investigate the effect and mechanism of Liraglutide on the spatial learning and memory function in type 2 diabetes mellitus(T2DM)rats.Methods SD rats were randomly divided into control group(NC),T2DM group(T2DM)and Liraglutide group(Lir).The ability of learning and memory was evaluated by Morris water maze method.Apoptosis of hippocampal neuron was tested by TUNEL staining.The mRNA expression levels of inflammatory cytokines TNF-α,IL-1βand IL-6 were measured by real time-PCR.The protein expressions of heme oxygenase-1(HO-1),NADPH oxidase 1(NOX1),protein B-cell lymphoma-2(Bcl-2)and Bcl2-associated X(Bax)in hippocampus tissues were determined by Western blot.Results Compared with T2DM group,the percent time in target quadrant was increased in Lir group(P<0.05),while the escape latency of day 3 to day 5 was significantly decreased in Lir group(P<0.05).The apoptosis of hippocampal neurons was reduced in Lir group,and the morphological changes,including hyperchromatic cytoplasm and karyopyknosis were alleviated.Compared with T2DM group,MDA content,mRNA level of TNF-α,IL-1βand IL-6,and protein expression of NOX1 and Bax were decreased(P<0.05),while T-AOC,SOD,HO-1 and Bcl-2 protein expression were increased in Lir group(P<0.05).Conclusions Liraglutide ameliorates diabetes-related learning and memory impairment by regulating antioxidant,anti-inflammatory and anti-apoptotic effects in hippocampus.