The effects of UCN2 on neural cell function of spinal cord injury rats facilitate post-injury neuronal regeneration

Spinal cord injury (SCI) is a devastating condition with high disability rates and lacks effective treatments. This study investigated the therapeutic potential of Urocortin 2 (UCN2) for promoting neurofunctional recovery. In a rat model of T10 spinal cord transection, daily intraperitoneal UCN2 treatment, initiated two days post-injury, significantly improved hindlimb motor function by day 14. We found that the UCN2 receptor, CRHR2, is expressed in neurons, astrocytes, and microglia. In vivo, UCN2 administration reduced neuronal apoptosis and neurofilament damage, suppressed microglial activation, and promoted the conversion of neurotoxic A1 astrocytes to a regenerative A2 phenotype. These beneficial effects were mediated by the activation of the cAMP-PKA signaling pathway, evidenced by the upregulation of PKA, CREB, and Bcl-2, and downregulation of NF-κB, RhoA, and Bax. Complementary in vitro experiments confirmed that UCN2 directly promotes axonal regeneration, inhibits neuronal apoptosis, enhances the secretion of GDNF from astrocytes, and suppresses the inflammatory NF-κB pathway in microglia. In conclusion, UCN2 facilitates axonal regeneration and functional recovery in SCI by activating the cAMP-PKA pathway, which in turn modulates neuronal survival, glial phenotype, and neuroinflammation, highlighting its significant therapeutic potential.