Tamoxifen Modulates Spinal Cord Injury Repair via Ccl2/ccr2 Axis and Its Mechanisms

Background: Spinal cord injury (SCI) represents a profoundly serious neurological disorder characterized by limited self-repair capabilities and accompanied by secondary inflammatory damage, rendering its treatment a pressing challenge in the field of medical science research. The estrogen receptor modulator Tamoxifen (TAM), owing to its neuroprotective and anti-inflammatory properties, is emerging as a potential option for the treatment of neural injury repair. Preliminary bioinformatics screening has revealed a significant increase in the expression of C-C motif chemokine ligand 2 (CCL2) and chemokine receptor 2 (CCR2) during the acute phase of SCI. TAM may exert therapeutic effects on SCI by inhibiting the activity of the CCL2/CCR2 axis, thereby influencing downstream pathways. Objective: This study aims to address the critical issue of secondary inflammatory damage hindering neural regeneration and repair following SCI. By investigating the regulatory effects of TAM on the CCL2/CCR2 axis and its downstream pathways, we seek to elucidate its molecular mechanisms and provide novel strategies for pharmacological intervention in secondary injuries associated with SCI. Methods: Utilizing bioinformatics techniques, we identified differentially expressed genes post-SCI and analyzed signaling pathways related to the CCL2/CCR2 axis. We assessed the expression levels of this axis following SCI and employed behavioral assays, RT-PCR, ELISA, and Western blotting to validate the effects of TAM administration on the CCL2/CCR2 axis, its downstream pathways, and molecular mechanisms in both LPS-induced microglial inflammation models and complete transection models of SCI. Furthermore, we utilized the CCR2 antagonist INCB3344 and the PPAR-γ antagonist GW9662 to further validate the relationships within these pathways. Results: TAM significantly reduced the expression of the CCL2/CCR2 axis in both in vitro and in vivo models following injury. By modulating this axis, TAM decreased NF-κB pathway expression and inhibited the secretion of inflammatory factors, facilitating the transition of microglia from a pro-inflammatory to an anti-inflammatory phenotype while activating the PPAR-γ pathway. Additionally, the activation of PPAR-γ reciprocally inhibited the expression of the CCL2/CCR2 axis. Conclusion: TAM may significantly alleviate secondary inflammatory responses following SCI through its modulation of the CCL2/CCR2 signaling pathway, exhibiting anti-apoptotic and anti-inflammatory effects. The findings of this study provide a theoretical foundation and experimental basis for the clinical application of TAM in SCI treatment research.