Lanthionine ketimine ester promotes locomotor recovery after spinal cord injury by reducing neuroinflammation and promoting axon growth

Ken Kotaka, Jun Nagai, Kenneth Hensley, Toshio Ohshima

    Research output: Contribution to journalArticle

    8 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)759-764
    Number of pages6
    JournalBiochemical and Biophysical Research Communications
    Volume483
    Issue number1
    DOIs
    Publication statusPublished - 2017 Jan 29

    Fingerprint

    Spinal Cord Injuries
    Axons
    Esters
    Recovery
    Growth
    Cicatrix
    Brain
    Sulfur Amino Acids
    Arginase
    Chemical activation
    Growth Inhibitors
    Macrophage Activation
    Microglia
    Neurites
    Histology
    Macrophages
    Neurology
    Metabolites
    Cultured Cells
    Serotonin

    Keywords

    • CRMP2
    • Lanthionine ketimine
    • Microglia
    • Neuroinflammation
    • Spinal cord injury

    ASJC Scopus subject areas

    • Biophysics
    • Biochemistry
    • Molecular Biology
    • Cell Biology

    Cite this

    Lanthionine ketimine ester promotes locomotor recovery after spinal cord injury by reducing neuroinflammation and promoting axon growth. / Kotaka, Ken; Nagai, Jun; Hensley, Kenneth; Ohshima, Toshio.

    In: Biochemical and Biophysical Research Communications, Vol. 483, No. 1, 29.01.2017, p. 759-764.

    Research output: Contribution to journalArticle

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