Activation of BDNF-TrkB-PI3K-AKT signaling pathway by Tong-Qiao-Huo-Xue Decoction facilitates nerve regeneration and mitigates cerebral ischemia-reperfusion injury

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-12 DOI:10.1016/j.phymed.2025.156966

Yuqin Peng , Hao Sun , Fan Xu , Haiyong Ye , Yan Wang , Xian Zhou , Dennis Chang , Ning Wang , Ping Huang

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Abstract

Background

Nerve regeneration is an important manifestation of self-repair mechanism after stroke. Tong-Qiao-Huo-Xue Decoction (TQHXD) has significant neuroprotective effects, but whether this effect is related to promoting nerve regeneration remains to be further explored.

Objective

To investigate the mechanisms underlying anti-cerebral ischemia-reperfusion injury and elucidate the reparative mechanism of TQHXD in ischemic stroke injury.

Methods

Model of middle cerebral artery obstruction(MCAO/R) in rats induced cerebral ischemia injury and then reperfusion was established using the thread embolus method, and cell model of oxygen glucose deprivation followed by glucose reoxygenation(OGD/R)injury was established in vitro to simulate cerebral ischemia reperfusion injury (CI/RI). The cerebral blood flow of rats was detected through the use of super-resolution blood flow meter and laser speckle, and the chemical components of TQHXD were analyzed using UPLC-Q-TOF/MS. The rats' learning and memory abilities were assessed through water maze and field experiments. The proliferation and differentiation of neural stem cells (NSCs) were assessed using flow cytometry, transwell migration assay, and scratch wound healing assay. Molecular docking probed into the binding affinity between the chemical components of TQHXD and BDNF. Pull-down experiments were conducted to validate the interaction between TrkB and PI3K.

Result

TQHXD demonstrates significant reduction in cerebral infarction volume in rats with an ischemia-reperfusion injury model, alleviates pathological brain tissue damage, improves rat learning and memory abilities, promotes NSCs proliferation and differentiation, up-regulates the expression of Nestin, PCNA, NeuN and DCX proteins in vivo and in vitro, as well as increases nerve ball diameter. It also mitigated OGD/R-induced NSCs injury under BDNF knockdown conditions.

Conclusions

Our findings suggest that TQHXD promotes the proliferation and differentiation of endogenous NSCs by activating the BDNF/TrkB/PI3K/AKT signaling pathway, which may serve as a potential therapeutic target for functional recovery after stroke.

Abstract Image

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通窍活血汤激活BDNF-TrkB-PI3K-AKT信号通路，促进神经再生，减轻脑缺血再灌注损伤

神经再生是脑卒中后自我修复机制的重要表现。通窍活血汤具有明显的神经保护作用，但这种作用是否与促进神经再生有关还有待进一步探讨。目的探讨TQHXD抗脑缺血再灌注损伤的机制，阐明TQHXD对缺血性脑卒中损伤的修复作用机制。方法采用线栓法建立脑缺血再灌注大鼠大脑中动脉阻塞（MCAO/R）模型，体外建立氧葡萄糖剥夺-葡萄糖再氧合（OGD/R）损伤细胞模型，模拟脑缺血再灌注损伤（CI/RI）。采用超分辨血流仪和激光散斑仪检测大鼠脑血流量，采用UPLC-Q-TOF/MS分析TQHXD的化学成分。通过水迷宫和实地实验对大鼠的学习记忆能力进行评估。采用流式细胞术、transwell迁移实验和划伤愈合实验评估神经干细胞（NSCs）的增殖和分化。分子对接探讨了TQHXD化学成分与BDNF之间的结合亲和力。下拉实验验证了TrkB和PI3K之间的相互作用。结果qhxd能显著减少缺血-再灌注损伤模型大鼠脑梗死体积，减轻病理性脑组织损伤，改善大鼠学习记忆能力，促进NSCs增殖和分化，上调体内外Nestin、PCNA、NeuN、DCX蛋白表达，增加神经球直径。它还减轻了BDNF敲低条件下OGD/ r诱导的NSCs损伤。结论TQHXD通过激活BDNF/TrkB/PI3K/AKT信号通路促进内源性NSCs的增殖和分化，可能是脑卒中后功能恢复的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.