td-5108 and Peripheral-Nerve-Injuries

Glycans attached to the cell surface via proteins or lipids or exposed in the extracellular matrix affect many cellular processes, including neuritogenesis, cell survival and migration, as well as synaptic activity and plasticity. These functions make glycans attractive molecules for stimulating repair of the injured nervous system. Yet, glycans are often difficult to synthesize or isolate and have the disadvantage to be unstable in a complex tissue environment. To circumvent these issues, we have screened a library of small organic compounds to search for structural and functional mimetics of the neurostimulatory glycan polysialic acid (PSA) and identified the 5-HT4 receptor agonist tegaserod as a PSA mimetic. The PSA mimicking activity of tegaserod was shown in cultures of central and peripheral nervous system cells of the mouse and found to be independent of its described function as a serotonin (5-HT4) receptor agonist. In an in vivo model for peripheral nerve regeneration, mice receiving tegaserod at the site of injury showed enhanced recovery compared to control mice receiving vehicle control as evidenced by functional measurements and histology. These data indicate that tegaserod could be repurposed for treatment of nervous system injuries and underscores the potential of using small molecules as mimetics of neurostimulatory glycans.

Topics: Animals; Biomimetics; Cells, Cultured; Cerebellum; Femoral Nerve; Ganglia, Spinal; Indoles; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Molecular; Motor Neurons; Nerve Regeneration; Neural Cell Adhesion Molecules; Neurons; Neuroprotective Agents; Peripheral Nerve Injuries; Recovery of Function; Schwann Cells; Serotonin 5-HT4 Receptor Agonists; Sialic Acids