Agarotetrol attenuates spinal cord injury by targeting PPARγ to modulate microglial activation

Secondary spinal cord injury (SCI) is characterized by sustained neuroinflammation and microglial activation. Agarotetrol (AH1), a principal bioactive component of agarwood, has demonstrated neuroprotective potential, yet its precise mechanism in SCI remains incompletely understood. A rat SCI model was established using vascular clip compression. AH1 was administered orally for 28 days. Behavioral tests, histology, immunofluorescence, Western blot, and ELISA were used to evaluate functional recovery, neuroinflammation, and microglial activation. In vitro, BV-2 cells were treated with AH1 and LPS to assess inflammatory responses and PPARγ involvement. AH1 treatment significantly improved motor function, reduced neuronal loss, and suppressed pro-inflammatory cytokine levels in SCI rats. In vitro, AH1 inhibited LPS-induced microglial activation and cytokine release. Mechanistically, AH1 directly bound to the PPARγ ligand-binding domain, enhanced PPARγ/PGC-1α/SRC-1 interaction, and promoted anti-inflammatory transcription. PPARγ knockdown abolished AH1's effects both in vivo and in vitro. AH1 attenuates neuroinflammation and promotes functional recovery after SCI by targeting PPARγ to modulate microglial polarization. These findings highlight AH1 as a potential therapeutic agent for SCI.