ABSTRACT Spinal cord injury (SCI) is a devastating condition with limited therapeutic options and a strong neuroinflammatory component that exacerbates tissue damage and impairs functional recovery. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and core component of the Polycomb Repressive Complex 2 (PRC2), has emerged as a key regulator of epigenetic modifications involved in neuroinflammation. In this study, we investigated the potential neuroprotective effects of GSK‐343, a selective EZH2 inhibitor, in a murine model of SCI induced by extradural compression. Female adult CD1 mice received intraperitoneal injections of GSK‐343 (1, 5, or 10 mg/kg) at 1‐ and 6‐h post‐injury. After 24 h, spinal cord tissues were collected and analyzed. GSK‐343 treatment significantly reduced histological damage, neuronal demyelination, and the expression of pro‐inflammatory markers, likely through modulation of the TRAF6/NF‐κB signaling pathway. Moreover, EZH2 inhibition attenuated innate immune responses, as evidenced by the reduction in mast cell infiltration, microglial activation, and MCP‐1 levels. These findings support the therapeutic potential of EZH2 inhibition as a novel epigenetic strategy to counteract neuroinflammation and promote early neuroprotection following SCI.
Kang et al. (Thu,) studied this question.