Therapeutic potential of a novel spirocyclic molecule in a murine model of peripheral nerve injury mediated via anti-inflammatory and neuroprotective properties.

BACKGROUND: Peripheral nervous system injury (PNI) is a leading cause of long-term disability worldwide, with traumatic damage to major nerves such as the sciatic nerve, facial nerve, and brachial plexus severely impairing motor function, reducing life expectancy, and predisposing to mood disorders, thereby imposing a substantial socioeconomic burden. Effective therapies to limit PNI-induced neural damage, particularly in sciatic nerve injury (SNI), remain inadequate, largely due to an incomplete understanding of the underlying molecular mechanisms. OBJECTIVE: To evaluate the efficacy of the CNS-active Spiro tricyclic compound IM-1725-RS-109a in improving motor deficits and modulating injury-related molecular markers in a mouse model of SNI. METHODS: Sciatic nerve injury was induced in C57BL/6NCrl mice using a standardized crush-force technique. The spiro compound IM-1725-RS-109a, previously shown to be effective in an ischemic stroke mouse model, was administered intraperitoneally at a daily dose of 5 mg/kg for 5 days following injury. RESULTS: Treatment with IM-1725-RS-109a significantly restored motor behavioral performance in OFT, rotarod, and pole tests in SNI mice compared with SNI group controls. Marked differences were observed between groups receiving treatment initiated at different post-injury time points. qRT-PCR and Western Blot analysis revealed significant increases in neurogenesis and reductions in inflammation in the treatment groups. CONCLUSION: IM-1725-RS-109a confers functional and molecular neuroprotection in a mouse model of sciatic nerve injury, supporting the peripheral neuroprotective and anti-inflammatory potential of CNS-active spiro tricyclic compounds. These findings suggest that the compound may be a promising candidate for further development as a therapeutic strategy for PNI.