DA-JC4对老龄大鼠术后神经炎症反应的影响

Effect of DA-JC4 on postoperative neuroinflammatory responses in aged rats

目的评价胰高血糖素样肽-1和葡萄糖依赖性促胰岛素多肽双受体激动剂DA-JC4对老龄大鼠术后神经炎症反应的影响。方法清洁级健康SD大鼠45只,雌雄不拘,21~23月龄,体重530~630 g,采用随机数字表法分为3组(n=15):假手术组(S组)、外科手术组(O组)和DA-JC4组(G组)。O组和G组水合氯醛麻醉下行剖腹探查术。G组分别于术毕即刻、术后24和48 h时腹腔注射DA-JC410 nmol/kg(溶于1 ml无菌生理盐水)。术后第3天采用Western blot法测定海马Bax、Bcl-2、活化的caspase-3、Beclin-1、微管相关蛋白1轻链3Ⅱ(LC3Ⅱ)、高迁移率族蛋白B1(HMGB1)、IL-1β和TNF-α的表达水平。术后第14-18天行Morris水迷宫实验测试认知功能。结果与S组比较,O组术后第15-18天、G组术后第18天逃离潜伏期延长,O组和G组穿越原平台次数减少,目标象限停留时间缩短,海马活化的caspase-3、Bax、LC3Ⅱ、HMGB1、IL-1β和TNF-α表达上调,Bcl-2、LC3Ⅱ和Beclin-1表达下调(P<0.05);与O组比较,G组术后第15-18天逃离潜伏期缩短,穿越原平台次数增加,目标象限停留时间延长,海马活化的caspase-3、Bax、HMGB1、IL-1β和TNF-α表达下调,Bcl-2、LC3Ⅱ和Beclin-1表达上调(P<0.05)。结论DA-JC4减轻老龄大鼠术后认知功能障碍的机制可能与抑制神经炎症反应有关。

Objective To evaluate the effect of glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist DA-JC4 on postoperative neuroinflammatory responses in aged rats.Methods Forty-five Sprague-Dawley rats,aged 21-23 months,weighing 530-630 g,provided by the Animal Experiment Center of Medical School of Zhengzhou University,were assigned into 3 groups(n=15 each)using a random number table method:sham operation group(group S),operation group(group O)and DA-JC4 group(group G).Rats underwent exploratory laparotomy under anesthesia with chloral hydrate in O and G groups.In group G,DA-JC410 nmol/kg(dissolved in 1 ml of sterile normal saline)was intraperitoneally injected immediately after the end of operation and at 24 and 48 h after operation.Western blot was used to determine the expression of hippocampal Bax,Bcl-2,activated caspase-3,Beclin-1,microtubule-associated protein 1 light chain 3Ⅱ(LC3Ⅱ),high-mobility group box 1 protein(HMGB1),interleukin-1beta(IL-1β)and tumor necrosis factor-alpha(TNF-α)on day 3 after surgery.The Morris water maze test was performed on days 14-18 after operation to assess the cognitive function.Results Compared with group S,the escape latency was significantly prolonged on days 15-18 after operation in group O and on day 18 after operation in group G,and the number of crossing the original platform was reduced,the time spent in the target quadrant was shortened,the expression of activated caspase-3,Bax,LC3Ⅱ,HMGB1,IL-1βand TNF-αin hippocampi was up-regulated,and the expression of Bcl-2,LC3Ⅱand Beclin-1 was down-regulated in O and G groups(P<0.05).Compared with group O,the escape latency was significantly shortened,and the number of crossing the original platform was increased,the time spent in the target quadrant was prolonged,the expression of activated caspase-3,Bax,LC3Ⅱ,HMGB1,IL-1βand TNF-αin hippocampi was down-regulated,and the expression of Bcl-2,LC3Ⅱand Beclin-1 was up-regulated in group G(P<0.05).Conclusion The mechanism by which DA-JC4 reduces postoperative cognitive dysfunction may be related to inhibiting neuroinflammatory responses in aged rats.