Role of Purmorphamine Administration in Acute Spinal Cord Injury

Spinal cord injury (SCI) affects approximately 18,000 individuals each year in the United States and remains a major cause of permanent neurological disability. Despite advances in surgical care and rehabilitation, there is currently no approved pharmacologic therapy that restores lost neural function or promotes meaningful regeneration after SCI. Traumatic SCI initiates a cascade of secondary injury mechanisms, including disruption of the blood-spinal cord barrier (BSCB), neuroinflammation, glial scarring, and progressive axonal and myelin loss, which together limit recovery. The Sonic Hedgehog (Shh) signaling pathway is a key regulator of vascular stability, inflammation, and neural stem cell activity in the adult central nervous system. Purmorphamine (PUR), a small-molecule agonist of the Shh pathway, has demonstrated therapeutic efficacy in multiple preclinical models of neurological disease by enhancing neuroprotection, suppressing inflammation, and promoting myelin repair. Importantly, PUR engages both endothelial and glial signaling mechanisms and activates endogenous neural stem/progenitor cells (eNSCs), a largely untapped intrinsic repair population in the injured spinal cord. The overall objective of this project is to determine whether systemic PUR treatment can provide a dual therapeutic benefit after SCI by attenuating acute injury mechanisms while promoting long-term endogenous repair. We hypothesize that PUR will stabilize the BSCB and suppress astrocyte-driven neuroinflammation in the acute phase of injury, while activating eNSCs to drive oligodendrocyte differentiation, remyelination, and functional recovery during the chronic phase. To test this hypothesis, we will use rigorously controlled rodent models of contusion SCI to evaluate the effects of PUR on vascular integrity, neuroinflammatory signaling, neural stem cell activation, tissue repair, and locomotor function. Our preliminary data demonstrate that short-course intravenous PUR significantly improves functional recovery and activates Shh signaling following SCI. Successful completion of this project will establish PUR as a clinically tractable, low-cost, small-molecule therapy that integrates neuroprotection with endogenous regeneration. These findings will provide a strong foundation for advancing PUR toward early-phase clinical trials and addressing the critical unmet need for effective pharmacologic treatment of SCI.