Mao-A Inhibition By Metaxalone Reverts Il-1 Beta-Induced Inflammatory Phenotype In Microglial Cells

Experimental and clinical studies have suggested that several neurological disorders are associated with the occurrence of central nervous system neuroinflammation. Metaxalone is an FDA-approved muscle relaxant that has been reported to inhibit monoamine oxidase A (MAO-A). The aim of this study was to investigate whether metaxalone might exert antioxidant and anti-inflammatory effects in HMC3 microglial cells. An inflammatory phenotype was induced in HMC3 microglial cells through stimulation with interleukin-1 beta (IL-1 beta). Control cells and IL-1 beta-stimulated cells were subsequently treated with metaxalone (10, 20, and 40 mu M) for six hours. IL-1 beta stimulated the release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), but reduced the anti-inflammatory cytokine interleukin-13 (IL-13). The upstream signal consisted of an increased priming of nuclear factor-kB (NF-kB), blunted peroxisome proliferator-activated receptor gamma (PPAR gamma), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) expression. IL-1 beta also augmented MAO-A expression/activity and malondialdehyde levels and decreased Nrf2 mRNA expression and protein levels. Metaxalone decreased MAO-A activity and expression, reduced NF-kB, TNF-alpha, and IL-6, enhanced IL-13, and also increased PPAR gamma, PGC-1 alpha, and Nrf2 expression. The present experimental study suggests that metaxalone has potential for the treatment of several neurological disorders associated with neuroinflammation.