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PO1-4-28

The role of ceramide kinase in the pathophysiology of multiple sclerosis

[Speaker] Ai Tanaka:1
[Co-author] Hiroyuki Nakamura:1, Toshihiko Murayama:1
1:Chiba university, Japan

Background
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease, which occurs in central nerve system. The mechanism of MS is thought to be the destruction of myelin sheath, but the cause is not clear. Furthermore, curative therapy has not been developed.
 Ceramide kinase (CerK) produces the bioactive sphingolipid ceramide-1-phosphate (C1P) and appears as a key enzyme for regulating inflammatory reaction, cell migration, and cell growth. CerK is expressed ubiquitously in mice, and its activity is the highest in the brain. Therefore, we have investigated the role of CerK in the pathophysiology of MS.

Methods
Administration of the copper chelator cuprizone (bis-cyclohexanone-oxaldihydrazone; CPZ) in mice provides a model of demyelination, and has been useful in understanding of MS. In this study, 8-week-old WT and CerK-knock out (KO) mice were exposed to 0.2% CPZ mixed with diet for 8 weeks.

Results
 It is known that administration of CPZ in mice for 8 weeks induces motor dysfunctions. In this study, the degree of CPZ-induced motor dysfunctions was higher in WT mice than that in CerK-KO mice. There was no difference in body weight between WT and CerK-KO mice, indicating that amount of CPZ-feeding might be almost same between both mice. To determine whether the degree of CPZ-induced demyelination is difference between WT and CerK-KO mice, we measured the thickness of corpus callosum by immunostaining. The thickness of corpus callosum between WT and CerK-KO mice was almost same. The degree of the reduction of corpus callosum induced by CPZ was lower in CerK-KO mice than that in WT mice. Next, we determined the levels of myelin associated proteins such as myelin basic protein (MBP) and 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNPase) in the hippocampus. We found that the expression of these proteins was significantly declined by feeding CPZ. The loss of these proteins induced by CPZ was lower in CerK-KO mice than that in WT mice.

Conclusions
 In this study, we revealed that CerK exacerbated the CPZ-induced demyelination in the mice model. Thus, CerK might be a new therapeutic target of MS.
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