Tegaserod mimics the neurostimulatory glycan polysialic acid and promotes nervous system repair

Abstract

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.

Porous and Nonporous Nerve Conduits: The Effects of a Hydrogel Luminal Filler With and Without a Neurite-Promoting Moiety

“…The final measured FBA for the NP-CollagenHNK compares favorably to the maximal FBA achieved in other studies using this animal model, even for much smaller noncritical size gaps. 28,32,38 This same trend was observed for the PLR, which, in comparison with the reflexive movements measured by the FBA, is a voluntary movement. 37 Significant improvement of the PLR for animals that received NP-CollagenHNK conduits was evident at 6 weeks postinjury (Fig.…”

The polysialic acid mimetics 5-nonyloxytryptamine and vinorelbine facilitate nervous system repair

“…Compound concentrations used were slightly higher than those with highest impact on neurite growth and neuronal migration in vitro 2627 and in the range of the PSA mimicking compound tegaserod21. Colominic acid was applied in parallel to compare the effects of PSA and the PSA mimicking compounds.…”

“…Peptide mimetics and small compound mimetics of PSA improved functional recovery following peripheral nerve and spinal cord injuries1718202125. These peptides and small compound mimetics of PSA offer advantages for development and approval of therapies applicable in humans.…”

Biodegradable Polymers: Medical Applications

“…Synthetic polypeptides such as amino acid homo-and copolymers are emerging biomaterials and are used in various biomedical applications including drug delivery, gene therapy, antibiotics, and tissue engineering (64,65). Polypeptides are inherently functional.…”