Limited effects of the REV-ERB agonist SR9009 after mouse spinal cord contusion: Reduced acute pathology with unaffected functional recovery and chronic white matter loss.

The ligand-regulated transcription factors REV-ERBα/NR1D1 and REV-ERBβ/NR1D2 are promising neuroprotective targets. Systemic administration of the REV-ERB agonist SR9009 has been shown to reduce neuroinflammation, limit tissue loss, and enhance functional recovery in several models of acute CNS injury. To evaluate its potential in spinal cord injury (SCI), a moderate contusion was induced at the T9 level in mice. SR9009 was administered intraperitoneally at 100 mg/kg per day (two 50 mg/kg doses at ZT1 and ZT12) for the first 7 days post-injury, when tissue damage is most pronounced in this model. At 3 days post-SCI, SR9009-treated mice exhibited reduced hematoma and decreased expression of transcripts associated with blood-spinal cord barrier disruption, inflammation, and cellular stress responses. However, hindlimb functional recovery remained unchanged throughout 6 weeks of follow-up, and no significant differences in white matter sparing were observed at study completion. These findings indicate that although SR9009 reduces acute activation of some secondary injury cascades, it does not promote long-term tissue preservation or functional recovery after contusive SCI in mice.