title: Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis.
abstract: 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 (mSOD1G93A mice).
  
  
  RESULTS
  Orally administered R723 had sufficient access to spinal cord tissue of mSOD1G93A mice and significantly reduced the number of Ly6c positive blood monocytes, as well as the expression levels of IFN-γ and nitric oxide synthase 2, inducible (iNOS) in the spinal cord tissue. R723 treatment did not alter the expression levels of Il-1β, 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 mSOD1G93A mice.
  
  
  CONCLUSIONS
  JAK2 inhibitor was not effective against ALS symptoms in mSOD1G93A 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.
authors.forename: Satoru
authors.initials: S
authors.lastname: Tada
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Okuno
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Hitoshi
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yasui
authors.forename: Josephe Archie
authors.initials: JA
authors.lastname: Honorat
authors.forename: Kazushiro
authors.initials: K
authors.lastname: Takata
authors.forename: Toru
authors.initials: T
authors.lastname: Koda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimagami
authors.forename: Choong
authors.initials: C
authors.lastname: Chi-Jing
authors.forename: Akiko
authors.initials: A
authors.lastname: Namba
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Saburo
authors.initials: S
authors.lastname: Sakoda
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikutani
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakatsuji
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects*; D009410:Nerve Degeneration / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2