Phenelzine, a small organic compound mimicking the functions of cell adhesion molecule L1, promotes functional recovery after mouse spinal cord injury.

Background: Neural cell adhesion molecule L1 contributes to nervous system development and maintenance by promoting neuronal survival, neuritogenesis, axonal regrowth/sprouting, myelination, and synapse formation and plasticity. L1 also enhances recovery after spinal cord injury and ameliorates neurodegenerative processes in experimental rodent models. Aiming for clinical translation of L1 into therapy we screened for and functionally characterized in vitro the small organic molecule phenelzine, which mimics characteristic L1 functions. Objective: The present study was designed to evaluate the potential of this compound in vivo in a mouse model of spinal cord injury. Methods and Results: In mice, intraperitoneal injection of phenelzine immediately after severe thoracic compression, and thereafter once daily for 6 weeks, improved hind limb function, reduced astrogliosis and promoted axonal regrowth/sprouting at 4 and 5 weeks after spinal cord injury compared to vehicle control-treated mice. Phenelzine application upregulated Ll expression in the spinal cord and stimulated the cognate L1-mediated intracellular signaling cascades in the spinal cord tissue. Phenelzine-treated mice showed decreased levels of pro-inflammatory cytokines, such as interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha in the injured spinal cord during the acute phase of inflammation. Conclusions: This study provides new insights into the role of phenelzine in L1-mediated neural functions and modulation of inflammation. The combined results raise hopes that phenelzine may develop into a therapeutic agent for nervous system injuries.