Drug pair-derived synergistic therapy of flavonoids luteolin and astragaloside IV promotes neural repair following spinal cord injury via antioxidant and neuroprotective effects

Abstract

Background Spinal cord injury (SCI) induces a damaging oxidative microenvironment exacerbating secondary injury. The traditional Chinese medicine (TCM) drug-pair Dangshen and Huangqi, known for antioxidant and neuroprotective effects, yields key components luteolin (Lut) and astragaloside IV (AST), both promising in oxidative stress-related neurological disorders but unexplored in combination for SCI.

Methods We investigated the synergistic antioxidant effects of Lut-AST combination therapy using an in vitro oxidative stress model in PC12 cells, and subsequently assessed its neuroprotective efficacy through behavioral assessments and histopathological analyses in a rat model of severe SCI. Finally, we utilized network pharmacology and molecular docking to predict and explore the potential of the Lut-AST drug pair for treating SCI through multi-target therapy.

Results Our study demonstrated that the Lut-AST drug pair synergistically attenuated oxidative stress-induced cytotoxicity. Lut-AST treatment effectively promoted nerve repair and functional recovery in SCI rats. A significant recovery of motor functions was observed accompanied by reduced accumulation of reactive oxygen species. Neuroinflammation and glial scars were largely alleviated, while the distribution of 5-hydroxytryptamine and neurofilament-positive nerve fibers was evidently increased.

Conclusion These findings confirm Lut-AST’s therapeutic efficacy in mitigating post-SCI oxidative stress and unveil novel insights into traditional Chinese medicine’s inherent multi-component synergistic interactions, suggesting potentiated outcomes through integrated antioxidant mechanisms and multi-target regulation. This study provides a paradigm for optimizing TCM-derived neuroprotective strategies by leveraging component synergy, informing novel combinatorial therapies for SCI management.

Keywords

luteolin / astragaloside IV / traditional Chinese medicine / spinal cord injury / oxidative stress / network pharmacology

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant No. 82402801), Hebei Provincial Health Commission, Hebei Medical Science Research Project (grant No. 20232139), Hebei Natural Science Foundation (grant No. H2023110901), Beijing-Tianjin-Hebei Basic Research Cooperation Project (grant No. J230012), the Youth Branch of Shandong Provincial Natural Science Foundation (grant No. ZR2024QH585), and the Key Project for the Development of Traditional Chinese Medicine Science and Technology in Shandong Province (grant No. Z20244804), and Tianjin Science and Technology Project (grant No. 21JCYBJC00920), and 2024 Open Project of Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine in Osteoarthritis Research, Cangzhou Science and Technology Leading Talent Project (Grant No. 20241203).

Author contributions

Wei Lin (Conceptualization), Peng Zhang (Resources), Defeng Liu (Data curation), Yihui Feng (Formal analysis), Dongdong Su (Validation), Xin Sun (Methodology), Na Yuan (Software), Xin Zhou (Resources), Zhen Liu (Resources), Shen Liu (Writing—review & editing), Huiqian Gao (Investigation), Liming Li (Su- pervision),Wenzhao Wang (Writing—review & editing), Ting Tian (Writing—review & editing), Jihui Zheng (Writing—review & edit- ing).

Supplementary material

Supplementary material is available at PCMEDI online.

Conflicts of interests

None declared.

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