核转录因子-κB-基质金属蛋白酶-9信号通路在糖尿病大鼠认知功能障碍中的作用

Role of NF-κB-MMP-9 pathway in diabetes-induced cognitive impairment in rats

目的探讨核转录因子-κB(NF-κB)-基质金属蛋白酶-9(MMP-9)通路在糖尿病(DM)大鼠认知功能障碍中的作用。方法采用55 mg/kg链脲激酶(STZ)单次腹腔注射诱导DM大鼠模型,随机分为3组(每组10只):对照组、DM组和DM吡咯烷二硫氨基甲酸酯(PDTC)治疗组(DM+PDTC组)。DM+PDTC组予以PDTC[150 mg/(kg·d)]持续灌胃6周。6周后采用Morris水迷宫检测学习记忆功能,选取上述同样处理的3组(每组6只)用于检测海马MMP-9及NF-κB的蛋白表达。结果 DM组的潜伏期在训练的第3、4、5天较对照组明显延长(P<0.05),而PDTC治疗可明显改善DM引起的潜伏期延长(P<0.05)。在空间探索试验中,目标象限的停留时间百分比比较,DM组较对照组明显下降(P<0.05),而DM+PDTC组较DM组明显增加(P<0.05)。DM组海马MMP-9和NF-κB的表达较对照组显著升高(P<0.05),而DM+PDTC组NF-κB的表达与对照组比较无显著性差异(P>0.05)。DM+PDTC组的MMP-9的表达较DM组显著降低(P<0.05),但较对照组仍显著升高(P<0.05)。结论DM可能通过激活NF-κB信号通路,从而部分上调MMP-9的表达,从而导致认知功能障碍的发生。

Objective To understand the potential role of NF-κB-MMP-9 pathway in diabetes-induced cognitive impairment in rats.Methods Streptozocin(STZ) was used to induce diabetes in Wistar rats.The rats were randomly selected and divided into three groups(n = 10 per group): non-diabetic control rats(control group),diabetic rats(DM group),and diabetic rats treated with NF-κB inhibitor pyrrolidine dithiocarbamate(PDTC) via gavage after diabetes induction for a period of 6 weeks(DM + PDTC group).Six weeks later,separate cohorts of rats were tested for cognitive function with Morris water maze task,or euthanized to assess MMP-9 and NF-κB levels in hippocampus(n = 6 per group).Results On the third,fourth and fifth day of training,the escape latency in DM group was significantly longer than that in control group(P < 0.05);however,chronic PDTC treatment reduced the latency significantly(P < 0.05).In probe test,the time spent in target quadrant in control group was significantly longer than that in DM group(P < 0.05),whereas the time spent in target quadrant in DM + PDTC group was significantly longer than that in DM group(P < 0.05).Protein levels of MMP-9 and NF-κB in DM group significantly elevated in comparison with those in control group(P <0.05).PDTC treatment decreased the levels of NF-κB(P <0.05).However,the hippocampal MMP-9 expression triggered by diabetes was only slightly(though significantly) attenuated while MMP-9 in DM + PDTC group was still higher than that in control group(P <0.05).Conclusions Diabetes-associated cognitive deficit stems partially from up-regulation of hippocampal MMP-9 via activation of NF-κB signaling pathway.