Rosiglitazone Attenuates Memory Impairment in Aged Rat with Diabetes by Inhibiting NF-kappa B Signal Pathway Activation
Rosiglitazone Attenuates Memory Impairment in Aged Rat with Diabetes by Inhibiting NF-kappa B Signal Pathway Activation
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DOI：
10.1055/s-0035-1559607
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发表时间：
2015-10-01
影响因子：
1.8
通讯作者：
Jun, L.
中科院分区：
文献类型：
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作者：
Fei, L.;Yong-Jun, H.;Jun, L.
虽然老年糖尿病患者的认知障碍很常见，但其机制尚不清楚，治疗方法也有限。本研究观察罗格列酮对老年糖尿病大鼠记忆障碍的影响。用链脲佐菌素诱导20~22月龄Wistar大鼠糖尿病。8周后，将糖尿病大鼠随机分为糖尿病模型组和罗格列酮治疗组，采用Morris水迷宫、实时荧光定量聚合酶链式反应和Western印迹分析方法对模型组和罗格列酮治疗组大鼠认知功能和脑损伤进行评估。另取同龄Wistar大鼠作为对照。在体外，用高糖和/或C反应蛋白(CRP)培养的大鼠嗜铬细胞株PC12观察罗格列酮的治疗作用。糖尿病诱导8周后，老龄大鼠出现明显且持续的高血糖、体重减轻、血清C反应蛋白水平升高和学习障碍。老年糖尿病大鼠脑内炎症反应增强与核因子B信号通路过度激活和海马炎性细胞因子(IL-6、TNF)上调有关。与糖尿病组比较，罗格列酮治疗组大鼠MWM逃避潜伏期和逃避距离明显缩短，血清CRP水平、炎性细胞因子水平和海马区NF-B信号通路过度激活部分恢复，认知功能障碍减轻。在体外，高糖显著激活了核因子-B信号通路，上调了炎性细胞因子。C反应蛋白协同促进高糖介导的效应。罗格列酮显著改善高糖和CRP.介导的作用，这些作用可被PPAR拮抗剂T0070907联合治疗而显著逆转。提示罗格列酮可能通过抑制老年糖尿病大鼠海马区核因子-B信号的激活，减少炎性细胞因子的表达，从而改善老年糖尿病大鼠的认知功能。
Although the cognitive impairment in geriatric diabetes is common, its mechanisms remain unclear and therapies are limited. The present study investigated the effects of rosiglitazone on memory impairment in aged rats with diabetes. Diabetes was induced by streptozotocin in aged Wistar rats of 20-22 months. Then, the diabetic rats were divided randomly into the diabetic model group and rosiglitazone treatment group for assessment of cognitive function and cerebral injury at 8 weeks using Morris water maze (MWM) paradigm, real-time PCR and western blot analysis. Wistar rats of the same age were also assessed as control. In vitro, the therapeutic effect of rosiglitazone was investigated using rat chromaffin cell line PC12 cultured with high glucose and/or C-reactive protein (CRP). 8 weeks after diabetes induction aged rats exhibited marked and persistent hyperglycemia, weight loss, higher level of serum CRP and learning impairments. Enhanced cerebral inflammation in aged rats with diabetes was associated with over-activation of the nuclear factor B (NF-B) signalling pathway and upregulation of inflammatory cytokines (IL-6, TNF) in the hippocampus. Compared with the diabetic group, level of serum CRP, inflammatory cytokines and over-activation of NF-B signalling pathway in the hippocampus were restored partially concomitant with attenuation of cognitive dysfunction indicated as markedly decreased escape latency and distance during MWM test in the rosiglitazone treatment group. In vitro, high glucose significantly activated NF-B signalling pathway and upregulated inflammatory cytokines. CRP synergistically promoted high glucose-mediated effects. Rosiglitazone significantly ameliorated the effects mediated by high glucose and CRP.These effects were significantly reversed by co-treatment with the PPAR antagonist T0070907. These results suggest that rosiglitazone can improve cognitive function in aged rats with diabetes by inhibiting the NF-B signal activation and decreasing the expressions of inflammatory cytokines in the hippocampus.