MAO-A Inhibition by Metaxalone Reverts IL-1β-Induced Inflammatory Phenotype in Microglial Cells.

Abstract

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-1β (IL-1β). Control cells and IL-1β-stimulated cells were subsequently treated with metaxalone (10, 20, and 40 µM) for six hours. IL-1β stimulated the release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) 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 (PPARγ), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression. IL-1β 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-α, and IL-6, enhanced IL-13, and also increased PPARγ, PGC-1α, and Nrf2 expression. The present experimental study suggests that metaxalone has potential for the treatment of several neurological disorders associated with neuroinflammation.

• Authors: Giovanni Pallio, Angela D'Ascola, Luigi Cardia, Federica Mannino, Alessandra Bitto, Letteria Minutoli, Giacomo Picciolo, Violetta Squadrito, Natasha Irrera, Francesco Squadrito, Domenica Altavilla
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 16 (Aug 05 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34445126 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• IL1B protein, human
• Interleukin-13
• Interleukin-1beta
• Interleukin-6
• Monoamine Oxidase Inhibitors
• Oxazolidinones
• PPAR gamma
• Tumor Necrosis Factor-alpha
• metaxalone
• Monoamine Oxidase

Topics

• Anti-Inflammatory Agents
• Cell Line
• Humans
• Inflammation (drug therapy, metabolism)
• Interleukin-13 (metabolism)
• Interleukin-1beta (metabolism)
• Interleukin-6 (metabolism)
• Microglia (drug effects, metabolism)
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (pharmacology)
• Oxazolidinones (pharmacology)
• PPAR gamma (metabolism)
• Phenotype
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)