Ginsenoside-Rh2 Promotes Functional Recovery after Spinal Cord Injury by Enhancing TFEB-Mediated Autophagy

Rongjie Liu; Liting Jiang; Yituo Chen; Jiaqin Shao; Kongbin Chen; Xiang Li; Junlei Lv; Wanta Cai; Haoxu Cai; Zhefan Zhu; Chenggui Wang; Kailiang Zhou; Jinfeng Huang; Jian Xiao; Wenfei Ni; Chenyu Wu

doi:10.1021/acs.jafc.4c02379

Ginsenoside-Rh2 Promotes Functional Recovery after Spinal Cord Injury by Enhancing TFEB-Mediated Autophagy

J Agric Food Chem. 2024 Jun 22. doi: 10.1021/acs.jafc.4c02379. Online ahead of print.

Authors

Rongjie Liu^{1

2

3}, Liting Jiang^{1

2

3}, Yituo Chen^{1

2

3}, Jiaqin Shao⁴, Kongbin Chen^{1

2

3}, Xiang Li^{1

2

3}, Junlei Lv^{1

2

3}, Wanta Cai^{1

2

3}, Haoxu Cai^{1

2

3}, Zhefan Zhu^{1

2

3}, Chenggui Wang^{1

2

3}, Kailiang Zhou^{1

2

3}, Jinfeng Huang^{1

2

3}, Jian Xiao⁴, Wenfei Ni^{1

2

3}, Chenyu Wu^{1

2

3

4}

Affiliations

¹ Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.
² Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China.
³ The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325027, China.
⁴ School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.

PMID: 38907713
DOI: 10.1021/acs.jafc.4c02379

Abstract

Background: Following spinal cord injury (SCI), autophagy plays a positive role in neuronal protection, whereas pyroptosis triggers an inflammatory response. Ginsenoside-Rh2 (GRh2), known for its neuroprotective effects, is considered a promising drug. However, the exact molecular mechanisms underlying these protective effects remain unclear. Aim of the Study: Explore the therapeutic value of GRh2 in SCI and its potential mechanisms of action. Materials and Methods: An SCI mouse model was established, followed by random grouping and drug treatments under different conditions. Subsequently, the functional recovery of SCI mice after GRh2 treatment was assessed using hematoxylin and eosin, Masson's trichrome, and Nissl staining, footprint analysis, Basso Mouse Scale scoring, and inclined plane tests. The expression levels of relevant indicators in the mice were detected using Western blotting, immunofluorescence, and a quantitative polymerase chain reaction. Network pharmacology analysis was used to identify the relevant signaling pathways through which GRh2 exerts its therapeutic effects. Results: GRh2 promoted functional recovery after SCI. GRh2 significantly inhibits pyroptosis by enhancing autophagy in SCI mice. Simultaneously, the neuroprotective effect of GRh2, achieved through the inhibition of pyroptosis, is partially reversed by 3-methyladenine, an autophagy inhibitor. Additionally, the increase in autophagy induced by GRh2 is mediated by the promotion of transcription factor EB (TFEB) nuclear translocation and dephosphorylation. Partial attenuation of the protective effects of GRh2 was observed after TFEB knockdown. Additionally, GRh2 can modulate the activity of TFEB in mice post-SCI through the EGFR-MAPK signaling pathway, and NSC228155 (an EGFR activator) can partially reverse the effect of GRh2 on the EGFR-MAPK signaling pathway. Conclusions: GRh2 improves functional recovery after SCI by upregulating TFEB-mediated autophagic flux and inhibiting pyroptosis, indicating its potential clinical applicability.

Keywords: EGFR-MAPK signaling pathway; TFEB; autophagy; ginsenoside-Rh2; pyroptosis; spinal cord injury.