title: Lanthionine ketimine ester promotes locomotor recovery after spinal cord injury by reducing neuroinflammation and promoting axon growth.
abstract: The mammalian central nervous system (CNS) has limited regenerative ability after injury, largely due to scar formation and axonal growth inhibitors. Experimental suppression of neuroinflammation encourages recovery from spinal cord injury (SCI), yet practical means for pharmacologically treating SCI have remained elusive. Lanthionine ketimine (LK) is a natural brain sulfur amino acid metabolite with demonstrated anti-neuroinflammatory and neurotrophic activities. LK and its synthetic brain-penetrating ethyl ester (LKE) promote growth factor-dependent neurite extension in cultured cell and suppress microglial activation in animal models of neurodegeneration. Thus far however, LKE has not been explored as a potential therapy for SCI. The present study investigated the hypothesis that systemic LKE could improve motor functional recovery after SCI in a mouse model. Intraperitoneal administration of LKE (100 mg/kg/d) after near-complete transect of spinal cord at the T7 level significantly improved motor function over a 4-week time course. Vehicle-treated mice, in contrast, demonstrated negligible functional recovery. In terms of histology, LKE treatment reduced pro-neuroinflammatory microglia/macrophage activation evidenced by quantitative Iba1 labeling and shifted the microglial phenotype toward a more neurotrophic M2 character evidenced by changes in the M2 marker arginase-1. This was correlated with less dense scar formation and more extensive axonal regrowth across the transection site demonstrated by 5-hydroxytryptamine (5HT) immunolabeling of raphespinal tract axons. These data provide evidence that LKE or similar compounds have potential therapeutic value for recovery after certain forms of SCI.
authors.affiliation: Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, TWIns, Tokyo, 162-8480, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kotaka
authors.affiliation: Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, TWIns, Tokyo, 162-8480, Japan; Research Fellow of Japan Society for the Promotion of Science, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Nagai
authors.affiliation: Department of Pathology, University of Toledo, College of Medicine, Toledo, OH, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hensley
authors.affiliation: Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, TWIns, Tokyo, 162-8480, Japan. Electronic address: ohshima@waseda.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
mesh_terms: D000603:Amino Acids, Sulfur / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001369:Axons / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000032:analysis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D020127:Recovery of Function / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D000603:Amino Acids, Sulfur; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D012701:Serotonin; C035499:lanthionine ketimine
keywords: CRMP2; Lanthionine ketimine; Microglia; Neuroinflammation; Spinal cord injury