Laquinimod Reduces Neuronal Injury Through Inhibiting Microglial Activation (P1.193)

OBJECTIVE: To investigate the mechanism by which laquinimod reduces brain atrophy and progression of disability observed in two Phase III trials in multiple sclerosis (MS). BACKGROUND: Persistent activation of microglia occurs in MS and contributes to the neurodegeneration processes. Thus, we investigated whether laquinimod alters properties of microglia in culture and in experimental autoimmune encephalomyelitis (EAE), and whether this reduced bystander neuronal injury. DESIGN/METHODS: Microglia was cultured from human surgical brain resections. EAE was induced in mice. RESULTS: The activation of human microglia in culture increased levels of several inflammatory molecules, and these elevations were attenuated by pre-treatment with laquinimod. Laquinimod prevented the decline in activated microglia of miR124a, a microRNA implicated in maintaining microglia quiescence, and it reduced the activity of several signaling pathways in 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 displayed reduced microglia/macrophage density and axonal injury. Remarkably, when laquinimod treatment was initiated well into the disease course when axons were degenerating, the progressive 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. In co-culture of microglia and neurons where microglia activation caused neuronal death, laquinimod decreased NO levels and prevented neurotoxicity. CONCLUSION: Laquinimod is a novel inhibitor of microglial activation that lowers microglia-induced pro-inflammatory cytokine secretion and neuronal cell death in culture and axonal injury/loss in EAE. Disclosure: Dr. Yong has received personal compensation for activities with Teva Neuroscience. Dr. Yong has received research support from Teva Neuroscience and Novartis. Dr. Mishra has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Keough has nothing to disclose. Dr. Silva has nothing to disclose. Dr. Fan has nothing to disclose. Dr. Sloka has nothing to disclose. Dr. Hayardeny Nisimov has received personal compensation for activities with Teva Neuroscience.