College of Pharmacology, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
Phytother Res. 2024 Jun;38(6):2619-2640. doi: 10.1002/ptr.8178. Epub 2024 Mar 15.
Salidroside, a principal bioactive component of Rhodiola crenulata, is neuroprotective across a wide time window in stroke models. We investigated whether salidroside induced neurogenesis after cerebral ischemia and aimed to identify its primary molecular targets. Rats, subjected to transient 2 h of middle cerebral artery occlusion (MCAO), received intraperitoneal vehicle or salidroside ± intracerebroventricular HSC70 inhibitor VER155008 or TrkB inhibitor ANA-12 for up to 7 days. MRI, behavioural tests, immunofluorescent staining and western blotting measured effects of salidroside. Reverse virtual docking and enzymatic assays assessed interaction of salidroside with purified recombinant HSC70. Salidroside dose-dependently decreased cerebral infarct volumes and neurological deficits, with maximal effects by 50 mg/kg/day. This dose also improved performance in beam balance and Morris water maze tests. Salidroside significantly increased BrdU/nestin, BrdU/DCX, BrdU/NeuN, BrdU/NeuN and BDNF cells in the peri-infarct cortex, with less effect in striatum and no significant effect in the subventricular zone. Salidroside was predicted to bind with HSC70. Salidroside dose-dependently increased HSC70 ATPase and HSC70-dependent luciferase activities, but it did not activate HSP70. HSC70 immunoreactivity concentrated in the peri-infarct cortex and was unchanged by salidroside. However, VER155008 prevented salidroside-dependent increases of neurogenesis, BrdU/NeuN cells and BDNF cells in peri-infarct cortex. Salidroside also increased BDNF protein and p-TrkB/TrkB ratio in ischemic brain, changes prevented by VER155008 and ANA-12, respectively. Additionally, ANA-12 blocked salidroside-dependent neurogenesis and increased BrdU/NeuN cells in the peri-infarct cortex. Salidroside directly activates HSC70, thereby stimulating neurogenesis and neuroprotection via BDNF/TrkB signalling after MCAO. Salidroside and similar activators of HSC70 might provide clinical therapies for ischemic stroke.
红景天苷是红景天的主要生物活性成分，它在中风模型中具有广泛的时间窗神经保护作用。我们研究了红景天苷是否能在脑缺血后诱导神经发生，并旨在确定其主要的分子靶点。将大鼠进行短暂的 2 小时大脑中动脉闭塞（MCAO）后，给予腹腔内载体或红景天苷±脑室 HSC70 抑制剂 VER155008 或 TrkB 抑制剂 ANA-12，持续 7 天。通过 MRI、行为测试、免疫荧光染色和 Western blot 检测红景天苷的作用。通过反向虚拟对接和酶促测定评估红景天苷与纯化重组 HSC70 的相互作用。红景天苷剂量依赖性地减少脑梗死体积和神经功能缺损，最大效应为 50mg/kg/天。该剂量还改善了平衡木和 Morris 水迷宫测试的表现。红景天苷显著增加了梗死周边皮质中的 BrdU/nestin、BrdU/DCX、BrdU/NeuN、BrdU/NeuN 和 BDNF 细胞，而在纹状体中的作用较小，在侧脑室下区中则没有显著作用。红景天苷被预测与 HSC70 结合。红景天苷剂量依赖性地增加了 HSC70 ATP 酶和 HSC70 依赖性荧光素酶的活性，但它没有激活 HSP70。HSC70 免疫反应性集中在梗死周边皮质，不受红景天苷影响。然而，VER155008 阻止了红景天苷依赖的神经发生、梗死周边皮质中的 BrdU/NeuN 细胞和 BDNF 细胞的增加。红景天苷还增加了缺血性脑内的 BDNF 蛋白和 p-TrkB/TrkB 比值，这一变化分别被 VER155008 和 ANA-12 所阻止。此外，ANA-12 阻断了红景天苷依赖的神经发生，并增加了梗死周边皮质中的 BrdU/NeuN 细胞。红景天苷直接激活 HSC70，从而通过 BDNF/TrkB 信号通路在 MCAO 后刺激神经发生和神经保护。红景天苷和类似的 HSC70 激活剂可能为缺血性中风提供临床治疗方法。
