The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, University Town, Guiyang, 550025, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guiyang, 550025, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guiyang, 550025, China.
The Maternal and Child Health Care Hospital of Guizhou Medical University, Guiyang, 550003, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guiyang, 550025, China.
Biochem Biophys Res Commun. 2023 Sep 3;671:246-254. doi: 10.1016/j.bbrc.2023.06.011. Epub 2023 Jun 3.
Vascular dementia (VaD), the second most common type of dementia, is attributed to lower cerebral blood flow. To date, there is still no available clinical treatment for VaD. The phenolic glucoside gastrodin (GAS) is known for its neuroprotective effects, but the role and mechanisms of action on VD remains unclear. In this study, we aim to investigate the neuroprotective role and underlying mechanisms of GAS on chronic cerebral hypoperfusion (CCH)-mediated VaD rats and hypoxia-induced injury of HT22 cells. The study showed that GAS relieved learning and memory deficits, ameliorated hippocampus histological lesions in VaD rats. Additionally, GAS down-regulated LC3II/I, Beclin-1 levels and up-regulated P62 level in VaD rats and hypoxia-injured HT22 cells. Notably, GAS rescued the phosphorylation of PI3K/AKT pathway-related proteins expression, which regulates autophagy. Mechanistic studies verify that YP-740, a PI3K agonist, significantly resulted in inhibition of excessive autophagy and apoptosis with no significant differences were observed in the YP-740 and GAS co-treatment. Meantime, we found that LY294002, a PI3K inhibitor, substantially abolished GAS-mediated neuroprotection. These results revealed that the effects of GAS on VaD are related to stimulating PI3K/AKT pathway-mediated autophagy, suggesting a potentially beneficial therapeutic strategy for VaD.
血管性痴呆（VaD）是第二大常见的痴呆类型，归因于脑血流量降低。迄今为止，仍然没有针对 VaD 的可用临床治疗方法。酚苷天麻素（GAS）以其神经保护作用而闻名，但 GAS 对 VaD 的作用和机制尚不清楚。在这项研究中，我们旨在研究 GAS 对慢性脑低灌注（CCH）介导的 VaD 大鼠和缺氧诱导的 HT22 细胞损伤的神经保护作用及其潜在机制。研究表明，GAS 缓解了 VaD 大鼠的学习和记忆缺陷，改善了海马组织学损伤。此外，GAS 下调了 VaD 大鼠和缺氧损伤的 HT22 细胞中 LC3II/I、Beclin-1 水平，并上调了 P62 水平。值得注意的是，GAS 挽救了 PI3K/AKT 通路相关蛋白表达的磷酸化，调节自噬。机制研究验证了 PI3K 激动剂 YP-740 显著抑制过度自噬和凋亡，而 YP-740 和 GAS 联合处理组没有观察到显著差异。同时，我们发现 PI3K 抑制剂 LY294002 显著消除了 GAS 介导的神经保护作用。这些结果表明，GAS 对 VaD 的影响与刺激 PI3K/AKT 通路介导的自噬有关，提示 GAS 可能是 VaD 的一种有益治疗策略。
