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

• DOI: 10.3233/rnn-170808
• Publication Date: 2018-06-08T15:15:33Z
• Authors: Rong Li; Sudhanshu Sahu; Melitta Schachner
• Keywords: Analysis of Variance; Biogenic Amines; Monoamine Oxidase Inhibitors; Time Factors; Dose-Response Relationship, Drug; MAP Kinase Signaling System; TOR Serine-Threonine Kinases; Myelin Basic Protein; Neural Cell Adhesion Molecule L1; Recovery of Function; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; 0302 clinical medicine; Gene Expression Regulation; Phenelzine; Animals; Cytokines; Female; Locomotion; Spinal Cord Injuries

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 L1 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-1β, interleukin-6, and tumor necrosis factor-α 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.