Xuefu Zhuyu decoction promotes synaptic plasticity by targeting miR-191a-5p/BDNF-TrkB axis in severe traumatic brain injury

Zhuan Pei; Xiaohang Guo; Fei Zheng; Zhaoyu Yang; Teng Li; Zhe Yu; Xuexuan Li; Xin Guo; Quan Chen; Chunyan Fu; Tao Tang; Dandan Feng; Yang Wang

doi:10.1016/j.phymed.2024.155566

Xuefu Zhuyu decoction promotes synaptic plasticity by targeting miR-191a-5p/BDNF-TrkB axis in severe traumatic brain injury

Phytomedicine. 2024 Mar 23:129:155566. doi: 10.1016/j.phymed.2024.155566. Online ahead of print.

Authors

Zhuan Pei¹, Xiaohang Guo², Fei Zheng³, Zhaoyu Yang⁴, Teng Li⁴, Zhe Yu¹, Xuexuan Li¹, Xin Guo⁵, Quan Chen¹, Chunyan Fu⁶, Tao Tang⁴, Dandan Feng⁷, Yang Wang⁸

Affiliations

¹ Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; NATCM Key Laboratory of TCM Gan, Xiangya Hospital, Central South University, Changsha 410008, PR China.
² School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, PR China.
³ The College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, PR China.
⁴ Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; NATCM Key Laboratory of TCM Gan, Xiangya Hospital, Central South University, Changsha 410008, PR China; Xiangya Hospital, Central South University, Jiangxi, Nanchang 330004, PR China.
⁵ The First Affiliated Hospital, Department of Child Healthcare, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China.
⁶ College of Pharmacy, Shaoyang University, Shaoyang 422100, PR China.
⁷ Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; NATCM Key Laboratory of TCM Gan, Xiangya Hospital, Central South University, Changsha 410008, PR China; Xiangya Hospital, Central South University, Jiangxi, Nanchang 330004, PR China. Electronic address: fengdandan373@csu.edu.cn.
⁸ Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; NATCM Key Laboratory of TCM Gan, Xiangya Hospital, Central South University, Changsha 410008, PR China; Xiangya Hospital, Central South University, Jiangxi, Nanchang 330004, PR China. Electronic address: wangyang_xy87@csu.edu.cn.

PMID: 38565001
DOI: 10.1016/j.phymed.2024.155566

Abstract

Background: Xuefu Zhuyu decoction (XFZYD) is a traditional Chinese herbal formula known for its ability to eliminate blood stasis and improve blood circulation, providing neuroprotection against severe traumatic brain injury (sTBI). However, the underlying mechanism is still unclear.

Purpose: We aim to investigate the neuroprotective effects of XFZYD in sTBI from a novel mechanistic perspective of miRNA-mRNA. Additionally, we sought to elucidate a potential specific mechanism by integrating transcriptomics, bioinformatics, and conducting both in vitro and in vivo experiments.

Methods: The sTBI rat model was established, and the rats were treated with XFZYD for 14 days. The neuroprotective effects of XFZYD were evaluated using a modified neurological severity score, hematoxylin and eosin staining, as well as Nissl staining. The anti-inflammatory effects of XFZYD were explored using quantitative real-time PCR (qRT-PCR), Western blot analysis, and immunofluorescence. Next, miRNA sequencing of the hippocampus was performed to determine which miRNAs were differentially expressed. Subsequently, qRT-PCR was used to validate the differentially expressed miRNAs. Target core mRNAs were determined using various methods, including miRNA prediction targets, mRNA sequencing, miRNA-mRNA network, and protein-protein interaction (PPI) analysis. The miRNA/mRNA regulatory axis were verified through qRT-PCR or Western blot analysis. Finally, morphological changes in the neural synapses were observed using transmission electron microscopy and immunofluorescence.

Results: XFZYD exhibited significant neuroprotective and anti-inflammatory effects on subacute sTBI rats' hippocampus. The analyses of miRNA/mRNA sequences combined with the PPI network revealed that the therapeutic effects of XFZYD on sTBI were associated with the regulation of the rno-miR-191a-5p/BDNF axis. Subsequently, qRT-PCR and Western blot analysis confirmed XFZYD reversed the decrease of BDNF and TrkB in the hippocampus caused by sTBI. Additionally, XFZYD treatment potentially increased the number of synaptic connections, and the expression of the synapse-related protein PSD95, axon-related protein GAP43 and neuron-specific protein TUBB3.

Conclusions: XFZYD exerts neuroprotective effects by promoting hippocampal synaptic remodeling and improving cognition during the subacute phase of sTBI through downregulating of rno-miR-191a-5p/BDNF axis, further activating BDNF-TrkB signaling.

Keywords: Bioinformatics analysis; MicroRNAs-mRNAs; Severe traumatic brain injury; Synaptic plasticity; Xuefu Zhuyu decoction; rno-miR-191a-5p/BDNF-TrkB.