米诺环素改善血管性痴呆大鼠认知功能障碍的机制研究

目的探索米诺环素是否在血管性痴呆导致的认知功能损害发生发展中发挥一定的神经保护作用，并进一步分析参与其中的相关分子机制。 方法SD大鼠随机分为假手术组、模型组和米诺环素治疗组。结扎双侧颈总动脉建立大鼠血管性痴呆模型，术后腹腔注射米诺环素（25，50 mg/kg），28 d后进行水迷宫行为学实验检测认知变化，HE染色和Western blotting分析大鼠海马神经细胞凋亡的相关机制。 结果（1）水迷宫认知功能测试显示，米诺环素能够显著缩短血管性痴呆大鼠寻找平台的潜伏期，并且明显延长在目标象限的停留时间，P<0.05为差异具有统计学意义。（2）HE染色显示米诺环素能够显著减轻模型组大鼠海马神经细胞损伤。（3）米诺环素治疗组含半胱氨酸的天冬氨酸蛋白水解酶-3（Caspase-3）蛋白表达水平及Bax/Bcl-2比值较模型组明显下降，P<0.05为差异具有统计学意义。（4）与模型组相比，米诺环素组磷脂酰肌醇3-激酶（PI3K）及磷酸化蛋白激酶B（p-AKT）蛋白表达水平明显升高，磷酸化糖原合酶激酶-3β（p-GSK-3β）蛋白表达却显著下降，P<0.05为差异具有统计学意义。 结论米诺环素通过激活PI3K/AKT信号通路，抑制该通路下游靶分子GSK-3β活性，减少海马神经细胞凋亡的发生，在神经细胞保护和改善认知功能障碍中发挥重要作用。

Minocycline prevents cognitive impairment in a rat model of vascular dementia

ObjectiveTo explore the neuroprotective effect of minocycline on cognitive impairment in a rat model of vascular dementia (VD) and its potential molecular mechanism. MethodsSD male rats were randomly divided into the sham-operation group, vascular dementia group and minocycline treated group. Rats were administered with minocycline by intraperitoneal injection after the surgery of bilateral common carotid artery occlusion. After 28 days, the Morris water maze test was carried out to test the spatial learning and memory ability of rats. The morphological changes of brain were observed by HE staining. Western blot was used to evaluate apoptosis mechanism of rat hippocampal neurons. Results(1)Minocycline treatment to VD rats significantly shortened the escape latency compared to the VD rats. In addition, Minocycline treated group spent more time in the target quadrant than the VD rats (P<0.05). (2)HE staining showed that minocycline could obviously protect the hippocampal neurons against damage in VD rats. (3)The protein expression of caspase-3 and Bax/Bcl-2 ratio in the minocycline administration group were significantly lower than those of the VD group (P<0.05). (4)Although minocycline decreased p-GSK-3β expression relatively to the VD group, the protein expression of PI3K and p-AKT in the minocycline treated group was significantly higher than that of the control group (P<0.05). ConclusionMinocycline protects against apoptosis of hippocampal neurons via the activation of PI3K/AKT signaling pathway and the inhibition of downstream target protein GSK-3β activity. Minocycline can play an important role in the protection of hippocampal neurons and the improvement of cognitive dysfunction.