title: Small Molecule Agonists of Cell Adhesion Molecule L1 Mimic L1 Functions In Vivo.
abstract: Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery after injury, leading to severe disabilities in motor functions and pain. Peripheral nerve injury impairs motor, sensory, and autonomic functions, particularly in cases where nerve gaps are large and chronic nerve injury ensues. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration after acute injury. We screened libraries of known drugs for small molecule agonists of L1 and evaluated the effect of hit compounds in cell-based assays in vitro and in mice after femoral nerve and spinal cord injuries in vivo. We identified eight small molecule L1 agonists and showed in cell-based assays that they stimulate neuronal survival, neuronal migration, and neurite outgrowth and enhance Schwann cell proliferation and migration and myelination of neurons in an L1-dependent manner. In a femoral nerve injury mouse model, enhanced functional regeneration and remyelination after application of the L1 agonists were observed. In a spinal cord injury mouse model, L1 agonists improved recovery of motor functions, being paralleled by enhanced remyelination, neuronal survival, and monoaminergic innervation, reduced astrogliosis, and activation of microglia. Together, these findings suggest that application of small organic compounds that bind to L1 and stimulate the beneficial homophilic L1 functions may prove to be a valuable addition to treatments of nervous system injuries.
authors.affiliation: Institut für Biosynthese Neuraler Strukturen, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum-Hamburg Eppendorf, Falkenried 94, 20251, Hamburg, Germany.
authors.forename: Hardeep
authors.initials: H
authors.lastname: Kataria
authors.affiliation: Institut für Biosynthese Neuraler Strukturen, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum-Hamburg Eppendorf, Falkenried 94, 20251, Hamburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Lutz
authors.affiliation: Institut für Biosynthese Neuraler Strukturen, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum-Hamburg Eppendorf, Falkenried 94, 20251, Hamburg, Germany.
authors.forename: Harshita
authors.initials: H
authors.lastname: Chaudhary
authors.affiliation: Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854, USA. schachner@stu.edu.cn.|Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou, Guangdong, 515041, China. schachner@stu.edu.cn.
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.affiliation: Institut für Biosynthese Neuraler Strukturen, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum-Hamburg Eppendorf, Falkenried 94, 20251, Hamburg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Loers
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000068736:Duloxetine Hydrochloride / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005267:Femoral Nerve / Q000187:drug effects / Q000293:injuries; D005960:Glucosides / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects; D039842:Neural Cell Adhesion Molecule L1 / Q000819:agonists* / Q000378:metabolism; D000071446:Neuronal Outgrowth / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D005960:Glucosides; D039842:Neural Cell Adhesion Molecule L1; D010455:Peptides; D054852:Small Molecule Libraries; D013267:Stilbenes; D000068736:Duloxetine Hydrochloride; D048049:Extracellular Signal-Regulated MAP Kinases; C058229:polydatin
keywords: Cell adhesion molecule L1; Femoral nerve injury; Neurite outgrowth; Neuronal survival; Small molecule; Spinal cord injury