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

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

doi:10.1016/j.phymed.2025.156966

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

Phytomedicine. 2025 Jun 12:145:156966. doi: 10.1016/j.phymed.2025.156966. Online ahead of print.

Authors

Yuqin Peng¹, Hao Sun², Fan Xu², Haiyong Ye², Yan Wang³, Xian Zhou⁴, Dennis Chang⁴, Ning Wang⁵, Ping Huang⁶

Affiliations

¹ Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, PR China; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese Medicine, Hefei Anhui, 230012, PR China; The Laboratory for Geriatric Care and Health, Anhui Academy of Chinese Medicine, Hefei Anhui, 230012, PR China.
² Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, PR China; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese Medicine, Hefei Anhui, 230012, PR China.
³ Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, PR China.
⁴ National Institute of Complementary Medicine, Western Sydney University, Westmead, NSW 2145, Australia.
⁵ Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, PR China; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese Medicine, Hefei Anhui, 230012, PR China; The Laboratory for Geriatric Care and Health, Anhui Academy of Chinese Medicine, Hefei Anhui, 230012, PR China. Electronic address: wnsci123@163.com.
⁶ Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, PR China; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese Medicine, Hefei Anhui, 230012, PR China. Electronic address: pingH0217@163.com.

PMID: 40578040
DOI: 10.1016/j.phymed.2025.156966

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.

Keywords: BDNF-TrkB-PI3K-AKT Signaling pathway; CI/RI; NSCs; Proliferation; TQHXD.