Tegaserod mimics the neurostimulatory glycan polysialic acid and promotes nervous system repair.
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.
New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA.
J
J
Bushman
Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
B
B
Mishra
New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA.
M
M
Ezra
European ScreeningPort GmbH, Schnackenburgalle 114, D-22525 Hamburg, Germany.
S
S
Gul
Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
C
C
Schulze
DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, MD 21702, USA.
S
S
Chaudhury
DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, MD 21702, USA.
D
D
Ripoll
DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, MD 21702, USA.
A
A
Wallqvist
New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA.
J
J
Kohn
Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany; Keck Center for Collaborative Neurosciences, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: schachner@biology.rutgers.edu.
M
M
Schachner
Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
G
G
Loers
D000818:Animals; D032701:Biomimetics; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects; D005267:Femoral Nerve / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D005727:Ganglia, Spinal / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D009416:Nerve Regeneration / Q000187:drug effects*; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D059348:Peripheral Nerve Injuries / Q000188:drug therapy / Q000473:pathology; D020127:Recovery of Function / Q000187:drug effects; D012583:Schwann Cells / Q000187:drug effects; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology; D012794:Sialic Acids / Q000378:metabolism*
D007211:Indoles; D019006:Neural Cell Adhesion Molecules; D018696:Neuroprotective Agents; D058828:Serotonin 5-HT4 Receptor Agonists; D012794:Sialic Acids; C021319:polysialic acid; C105050:tegaserod
Drug repurposing; Glycan; Mimetic; Peripheral nerve; Polysialic acid; Regeneration; Tegaserod