Laquinimod reduces neuroaxonal injury through inhibiting microglial activation

Abstract

ObjectiveLaquinimod 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.MethodsMicroglia were cultured from human brains. EAE was induced in mice.ResultsThe 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.InterpretationLaquinimod is a novel inhibitor of microglial activation that lowers microglia-induced neuronal death in culture and axonal injury/loss in EAE.

Clinical quantitative susceptibility mapping (QSM): Biometal imaging and its emerging roles in patient care

“…QSM measurement of chronic inflammation in MS lesions that appear stable on conventional MRI but have a high burden of lesional microglial activation are of significant therapeutic and diagnostic importance. Several compounds that are either FDA approved (Tecfidera) or under development (Laquinimod (170) and Siponimod (171)) have been shown to impact microglial activation (172,173). QSM can be utilized to monitor these therapies for their ability to mitigate iron accumulation in microglia.…”

Microglial Phenotypes and Functions in Multiple Sclerosis

“…Mice treated with laquinimod before onset of clinical signs had marked reduction in microglia/macrophage density and axonal injury/loss. In addition, treatment with laquinimod halted disease progression and production of inducible nitric oxide, thus attenuating the neurodegeneration associated with EAE (Mishra et al 2014).…”

“…In vivo studies have shown that laquinimod reduces leukocyte infiltration to the CNS, induces a shift from cytotoxic Th1 to Th2/ 3, and dampens the Th17 responses in the EAE model (Yang et al 2004;Wegner et al 2010). In the context of microglia, laquinimod is a novel inhibitor of microglial activation that decreases microglial-induced neuronal cell death in vitro and axonal degeneration/loss in vivo (Mishra et al 2014). In EAE, axonal injury is often correlated with the accumulation of microglia/macrophages in the spinal cord.…”

Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor

“…The influence of laquinimod on the immune system was studied in experimental autoimmune encephalomyelitis (EAE) (4)(5)(6)(7)(8)(9)(10)(11)(12), an autoimmune disease mediated by proinflammatory myelinreactive lymphocytes that cause CNS inflammation leading to demyelination and axonal loss. Laquinimod has also been effective in the treatment of other models of autoimmune diseases, specifically experimental autoimmune neuritis (13,14), lupus nephritis (15), and colitis (16).…”