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Lanthionine ketimine ester provides benefit in a mouse model of multiple sclerosis
Author(s) -
Dupree Jeffrey L.,
Polak Paul E.,
Hensley Kenneth,
Pelligrino Dale,
Feinstein Douglas L.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13114
Subject(s) - myelin , microglia , chemistry , experimental autoimmune encephalomyelitis , myelin oligodendrocyte glycoprotein , spinal cord , multiple sclerosis , neurite , biochemistry , central nervous system , microbiology and biotechnology , biology , immunology , endocrinology , neuroscience , inflammation , in vitro
Lanthionine ketimine ( LK ) is a natural sulfur amino acid metabolite which binds to collapsin response mediator protein‐2 ( CRMP 2), an abundant brain protein that interacts with multiple partners to regulate microtubule dynamics, neurite growth and retraction, axonal transport, and neurotransmitter release. LK ethyl‐ester ( LKE ) is a cell‐permeable synthetic derivative that promotes neurogenesis, suppresses nitric oxide production from microglia, and reduces neurotoxicity of microglia‐conditioned medium. These properties led us to test the effects of LKE in experimental autoimmune encephalomyelitis ( EAE ), a commonly used mouse model of multiple sclerosis. Female C57Bl/6 mice were immunized with myelin oligodendrocyte glycoprotein peptide 35–55 to develop a chronic disease. LKE was provided in the chow at 100 ppm, ad libitum beginning when the mice reached moderate clinical signs. Over the following 4 weeks the LKE ‐treated mice showed a significant reduction in clinical signs compared to vehicle‐treated mice. LKE dose dependently reduced IFN γ production from splenic T cells, but had no effect on IL ‐17 production suggesting protective effects were mediated within the CNS . Electron microscopy revealed that, compared to sham mice, EAE mice had significant neurodegeneration in both the optic nerve and spinal cord, which was reduced in the LKE ‐treated mice. In contrast only minimal disruption of myelin was observed at this time point. In the optic nerve, measurements of axon caliber and myelin thickness showed little changes between sham and EAE mice, however, treatment with LKE increased the percentage of axons with thicker myelin and with larger axon calibers. In the spinal cord, only smaller effects of LKE on myelin thickness were observed. The effects of LKE were associated with a reduced relative level of phosphorylated CRMP 2 to CRMP 2. Together, these results demonstrate that LKE reduces neurodegeneration in a chronic EAE model of MS , which could have translation potential for treatment of progressive forms of MS .Only few drugs have been shown to reduce neurodegeneration in multiple sclerosis (MS). We report that LKE (lanthionine ketimine ethyl‐ester, a derivative of the amino acid lanthionine) reduced clinical signs in a mouse model of chronic MS, and also reduced neurodegeneration and axonal damage in the spinal cord and optic nerve (shown in the graphic). These effects were associated with changes in levels and phosphorylation state of CRMP2 (collapsin response mediator protein 2), which has known actions on axon growth. These findings suggest that LKE may be a candidate for testing in progressive forms of MS.