Laquinimod reduces neuroaxonal injury through inhibiting microglial activation. (26th May 2014)

• Record Type: Journal Article
• Authors: Mishra, Manoj Kumar; Wang, Janet; Keough, Michael B.; Fan, Yan; Silva, Claudia; Sloka, Scott; Hayardeny, Liat; Brück, Wolfgang; Yong, V. Wee
• Is Part Of: Annals of clinical and translational neurology. Volume 1:Number 6(2014)
• Page Start: 409
• Page End: 422
• Publication Date: 2014-05-26
• Subjects: Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1002/acn3.67
• Languages: English
• ISSNs: 2328-9503

Abstract

<abstract abstract-type="main" id="acn367-abs-0001"> <title>Abstract</title> <sec id="acn367-sec-0001" sec-type="section"> <title>Objective</title> <p>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.</p> </sec> <sec id="acn367-sec-0002" sec-type="section"> <title>Methods</title> <p>Microglia were cultured from human brains. EAE was induced in mice.</p> </sec> <sec id="acn367-sec-0003" sec-type="section"> <title>Results</title> <p>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.</p> </sec> <sec id="acn367-sec-0004" sec-type="section"> <title>Interpretation</title> <p>Laquinimod is a novel inhibitor of microglial activation that lowers microglia‐induced neuronal death in culture and axonal injury/loss in EAE.</p> </sec> </abstract>