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Abstract：
Chronic cerebral hypoperfusion is an important risk factor for vascular dementia (VaD) and other brain dysfunctions, for which there are currently no effective medications available. In the present study, we investigated the potential therapeutic effects of cornel iridoid glycoside (CIG) on VaD in rats modeled by permanent bilateral common carotid artery ligation (2-vessel occlusion, 2VO). The object recognition test (ORT) and Morris water maze (MWM) test were conducted to evaluate the learning and memory function. Western blot analysis and immunohistochemical staining were used to detect the expression of related proteins. Results showed that intragastric administration of CIG (30, 60, and 120 mg/kg) for 3 months significantly increased the discrimination index in ORT and decreased the escape latency in MWM test, ameliorating the learning and memory deficit in 2VO rats. Further data indicated that CIG increased the expression of neurotrophic factors (NGF and BDNF) and their receptors (TrkA and TrkB), glutamate receptor subunits (NMDAR1 and GluR2) in the cerebral cortex and hippocampus of 2VO rats. In addition, CIG elevated the expression of PI3K subunits p110α and p85, further upregulated the phosphorylation of Akt, GSK3β-ser9 and CREB in the cerebral cortex and hippocampus at 3 months after 2VO surgery. Collectively, CIG treatment improved learning and memory deficit induced by chronic cerebral hypoperfusion via increasing neurotrophic factors thus protecting glutamate receptors and activating PI3K/Akt/GSK3β/CREB signaling pathway in rats. These results suggest that CIG may be beneficial to VaD therapy.
摘要：
慢性脑低灌注是血管性痴呆（VaD）和其他脑功能障碍的重要危险因素，目前尚无有效的药物。在本研究中,我们研究了通过永久性双侧颈总动脉结扎（2血管闭塞，2VO）。进行物体识别测试（ORT）和Morris水迷宫（MWM）测试以评估学习和记忆功能。采用Westernblot分析和免疫组化染色检测相关蛋白的表达。结果表明，灌胃CIG（30、60和120mg/kg）3个月显着提高了ORT的辨别指数，并降低了MWM测试的逃避潜伏期。改善2VO大鼠学习记忆障碍。进一步的数据表明CIG增加了神经营养因子（NGF和BDNF）及其受体（TrkA和TrkB）的表达，2VO大鼠大脑皮质和海马中的谷氨酸受体亚基（NMDAR1和GluR2）。此外,CIG升高PI3K亚基p110α和p85的表达，进一步上调Akt的磷酸化，2VO手术后3个月，大脑皮层和海马中的GSK3β-ser9和CREB。总的来说，CIG治疗通过增加神经营养因子从而保护谷氨酸受体和激活PI3K/Akt/GSK3β/CREB信号通路改善慢性脑低灌注所致大鼠学习记忆障碍。这些结果表明CIG可能对VaD治疗有益。
