糖尿病并发抑郁症大鼠海马血脑屏障结构的损伤及其机制

目的：研究糖尿病并发抑郁症大鼠海马血脑屏障结构关键蛋白紧密连接蛋白（ZO-1）、基底膜蛋白（CoIV）、周细胞蛋白（a-SMA）的表达情况及其损伤机制。方法：采用高脂灌胃14 d后，再尾静脉注射链脲佐菌素（STZ，38mg/kg），随机分为2组（n=15）：糖尿病组和糖尿病并发抑郁症组；正常大鼠随机分为2组（n=15）：空白对照组和抑郁症组。糖尿病组与空白对照组正常饲养，糖尿病并发抑郁症组和抑郁症组慢性不可预知性应激28 d。检测各组大鼠血糖值的变化，Open-field及Morris实验评价大鼠行为学变化，透射电子显微镜观察大鼠海马血脑屏障形态学改变，免疫组化法检测大鼠海马血脑屏障关键蛋白ZO-1、CoIV、a-SMA表达情况。结果：与空白对照组比较，糖尿病并发抑郁症组大鼠血糖异常升高，自主活动次数减少，逃避潜伏期延长，空间探索时间减少（P < 0.05，P < 0. 01）；海马血脑屏障内皮模糊，毛细血管管腔狭窄，周边胶质细胞终足水肿，ZO-1、α-SMA表达显著减少（P < 0. 05），CoIV的表达显著增加（P < 0.05）；与糖尿病组比较，糖尿病并发抑郁症组大鼠自主活动次数显著减少（P < 0. 01），逃避潜伏期延长（P < 0.05），海马血脑屏障毛细血管管腔更为狭窄、胶质细胞终足水肿更为明显，a-SMA表达显著下降（P< 0.05）。结论：糖尿病并发抑郁症血脑屏障关键蛋白ZO-1、CoIV、α-SMA表达紊乱可能是其结构损伤发生机制之一。

Damages and its mechanism of the blood brain barrier in rats with diabetes mellitus with depression

Objective: To investigate the expressions of key proteins type IV collagen (CoIV), zonula occludens-1(ZO-1), α-smooth muscle actin(a-SMA) and the mechanisms of the structural injuries of the blood brain barrier in the hippocampus of diabetic rats with depression. Methods: After 14 days of high-fat diet, the rats were treated with streptozotocin (STZ, 38 mg/kg, iv). Then, the animals were randomly divided into 2 groups (n=15):the diabetic group and the diabetes mellitus with depression group. The normal rats were randomly divided into 2 groups(n=15):the control group and the depression group. Diabetic group and control group were kept in normal conditions. The diabetes mellitus with depression group and the depression group were treated with chronic unpredictable stress for 28 days. The levels of blood glucose were detected. The behavior changes of rats were evaluated by open-field test and Morris test. The blood brain barrier morphological changes were observed under the electron microscope. The expressions of CoIV, ZO-1 and a-SMA in rat hippocampal blood-brain barrier were detected by immunocytochemistry. Results: Compared with control group, the level of blood glucose was increased,the number of autonomic activity was decreased, the escape latencies were significantly longer in the Morris water maze test, as well as the space exploration times were shortened in the diabetes mellitus with depression group (P<0.05, P<0.01). The endothelial cells of the hippocampus were blurred, the capillary lumen was narrow, and the peripheral glial cells were edema, the expressions of ZO-1 and a-SMA were decreased(P <0.05), while the expression of CoIV was increased(P <0.05). Compared with diabetic group, the number of autonomic activity in the diabetes mellitus with depression group was significantly decreased (P<0.01), the escape latencies were longer (P<0.05), the blood brain barrier capillary lumen was more narrow and the glial cell terminal edema was more obvious, the expression of a-SMA was decreased(P<0.05). Conclusion: The abnormal expressions of ZO-1, CoIV and -SMA, key proteins in the hippocampal blood brain barrier, may be involved in the mechanisms of structural damages of the blood brain barrier in diabetes mellitus with depression.