title: Laquinimod reduces neuroaxonal injury through inhibiting microglial activation.
abstract: OBJECTIVE
  Laquinimod is an emerging oral medication for multiple sclerosis (MS) that reduces brain atrophy and progression of disability in two Phase III clinical trials. The mechanism of these effects is unclear. Persistent activation of microglia occurs in MS and contributes to injury. Thus, we investigated whether laquinimod alters properties of microglia in culture and in experimental autoimmune encephalomyelitis (EAE), and whether this reduces neurodegeneration.
  
  
  METHODS
  Microglia were cultured from human brains. EAE was induced in mice.
  
  
  RESULTS
  The activation of human microglia increased levels of several pro- and anti-inflammatory cytokines and these elevations were attenuated by pretreatment with laquinimod. Laquinimod prevented the decline in activated microglia of miR124a, a microRNA implicated in maintaining microglia quiescence, and reduced the activity of several signaling pathways (Jun-N-terminal kinase, ribosomal S6 kinase, and AKT/protein kinase B) in activated microglia. In EAE, axonal injury correlated with accumulation of microglia/macrophages in the spinal cord. EAE mice treated with laquinimod before onset of clinical signs subsequently had reduced microglia/macrophage density and axonal injury. Remarkably, when laquinimod treatment was initiated well into the disease course, the progressive demyelination, and axonal loss was halted. Besides inflammatory molecules associated with microglia, the level of inducible nitric oxide (NO) synthase capable of producing free radical toxicity was attenuated by laquinimod in EAE mice. Finally, in coculture where microglia activation caused neuronal death, laquinimod decreased NO levels, and neurotoxicity.
  
  
  CONCLUSIONS
  Laquinimod is a novel inhibitor of microglial activation that lowers microglia-induced neuronal death in culture and axonal injury/loss in EAE.
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary Calgary, Alberta, Canada.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Mishra
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary Calgary, Alberta, Canada.
authors.forename: Janet
authors.initials: J
authors.lastname: Wang
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary Calgary, Alberta, Canada.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Keough
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary Calgary, Alberta, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary Calgary, Alberta, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.affiliation: Grand River Hospital Kitchener, Ontario, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Sloka
authors.affiliation: Teva Pharmaceutical Industries Ltd Petach Tikva, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Hayardeny
authors.affiliation: Department of Neuropathology, University Medical Center Göttingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary Calgary, Alberta, Canada.
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong