Journal
JOURNAL OF NEUROINFLAMMATION
Volume 11, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12974-014-0179-2
Keywords
Amyotrophic lateral sclerosis; SOD1-G93A transgenic mice; R723; Janus kinase 2; JAK2 inhibitor; Neuroinflammation; Interferon gamma; M1/M2 microglia
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Funding
- Inochi-no-Iro ALS Research Grant
- Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) [24790883]
- MEXT [20229007, 24111531]
- Health Labour Sciences Research Grant from the Japanese Ministry of Health, Labour and Welfare
- Health Labour Sciences Research Grant for Intractable Diseases from the Japanese Ministry of Health, Labour and Welfare [22590931]
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Background: Accumulating evidence has shown that the inflammatory process participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), suggesting a therapeutic potential of anti-inflammatory agents. Janus kinase 2 (JAK2), one of the key molecules in inflammation, transduces signals downstream of various inflammatory cytokines, and some Janus kinase inhibitors have already been clinically applied to the treatment of inflammatory diseases. However, the efficacy of JAK2 inhibitors in treatment of ALS remains to be demonstrated. In this study, we examined the role of JAK2 in ALS by administering a selective JAK2 inhibitor, R723, to an animal model of ALS (mSOD1(G93A) mice). Findings: Orally administered R723 had sufficient access to spinal cord tissue of mSOD1(G93A) mice and significantly reduced the number of Ly6c positive blood monocytes, as well as the expression levels of IFN-gamma and nitric oxide synthase 2, inducible (iNOS) in the spinal cord tissue. R723 treatment did not alter the expression levels of Il-1 beta, Il-6, TNF, and NADPH oxidase 2 (NOX2), and suppressed the expression of Retnla, which is one of the markers of neuroprotective M2 microglia. As a result, R723 did not alter disease progression or survival of mSOD1(G93A) mice. Conclusions: JAK2 inhibitor was not effective against ALS symptoms in mSOD1(G93A) mice, irrespective of suppression in several inflammatory molecules. Simultaneous suppression of anti-inflammatory microglia with a failure to inhibit critical other inflammatory molecules might explain this result.
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