Monoamine Oxidase Inhibitors: A Review of Their Anti-Inflammatory Therapeutic Potential and Mechanisms of Action

Abstract

Chronic inflammatory diseases are debilitating, affect patients’ quality of life, and are a significant financial burden on health care. Inflammation is regulated by pro-inflammatory cytokines and chemokines that are expressed by immune and non-immune cells, and their expression is highly controlled, both spatially and temporally. Their dysregulation is a hallmark of chronic inflammatory and autoimmune diseases. Significant evidence supports that monoamine oxidase (MAO) inhibitor drugs have anti-inflammatory effects. MAO inhibitors are principally prescribed for the management of a variety of central nervous system (CNS)-associated diseases such as depression, Alzheimer’s, and Parkinson’s; however, they also have anti-inflammatory effects in the CNS and a variety of non-CNS tissues. To bolster support for their development as anti-inflammatories, it is critical to elucidate their mechanism(s) of action. MAO inhibitors decrease the generation of end products such as hydrogen peroxide, aldehyde, and ammonium. They also inhibit biogenic amine degradation, and this increases cellular and pericellular catecholamines in a variety of immune and some non-immune cells. This decrease in end product metabolites and increase in catecholamines can play a significant role in the anti-inflammatory effects of MAO inhibitors. This review examines MAO inhibitor effects on inflammation in a variety of in vitro and in vivo CNS and non-CNS disease models, as well as their anti-inflammatory mechanism(s) of action.

Monoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling

“…Induction of P/DAMP signaling drives epithelial cells to express pro-inflammatory cytokines and chemokines such as interleukin-1 β (IL-1β), tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) ( Borish and Steinke, 2003 ; Kugelberg, 2014 ; Groeger and Meyle, 2019 ; Plemmenos et al, 2021 ). Significant evidence supports that reduction of monoamine oxidase enzyme function by MAO inhibitors decreases innate immune-based cytokine signaling and positively improves disease progression ( Ostadkarampour and Putnins, 2021 ).…”

“…A number of studies have also demonstrated that MAO inhibitors decrease gene and protein expression of a number of pro-inflammatory cytokines and chemokines. This reduction in drivers of inflammation may have therapeutic potential ( Ostadkarampour and Putnins, 2021 ).…”

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“…MAO inhibitors also increase biogenic amines such as dopamine and this increase can modify immune responses (Ostadkarampour and Putnins, 2021). Dopamine signaling can act in a receptor-dependent and also receptorindependent manner.…”

“…Induction of P/DAMP signaling drives epithelial cells to express pro-inflammatory cytokines and chemokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) (Borish and Steinke, 2003;Kugelberg, 2014;Groeger and Meyle, 2019;Plemmenos et al, 2021). Significant evidence supports that reduction of monoamine oxidase enzyme function by MAO inhibitors decreases innate immune-based cytokine signaling and positively improves disease progression (Ostadkarampour and Putnins, 2021).…”

“…MAO inhibitors are MAO-A, MAO-B or MAO-A/B selective and bind in a reversible or irreversible manner. They reduce metabolic end products such as hydrogen peroxide, aldehydes and ammonium but also increase levels of catecholamines such as dopamine (Eisenhofer et al, 2004;Ostadkarampour and Putnins, 2021). Dopamine modulates inflammatory responses in nonneuronal cells such as lymphocytes and epithelial cells as well (Bergquist et al, 1994;Goldstein et al, 1995;Adir et al, 2004;Qiu et al, 2005;Matt and Gaskill, 2020).…”