Inhibition of monoamine oxidase B prevents reactive astrogliosis and scar formation in stab wound injury model

Abstract

Reactive astrocytes manifest molecular, structural, and functional alterations under various pathological conditions. We have previously demonstrated that the reactive astrocytes of the stab wound injury model (STAB) display aberrant cellular gamma‐aminobutyric acid (GABA) content and tonic GABA release, whereas the active astrocytes under enriched environment (EE) express high levels of proBDNF. However, the role of monoamine oxidase B (MAO‐B) in reactive astrogliosis and hypertrophy still remains unknown. Here, we investigate the role of MAO‐B, a GABA‐producing enzyme, in reactive astrogliosis in STAB. We observed that the genetic removal of MAO‐B significantly reduced the hypertrophy, scar formation, and GABA production of reactive astrocytes, whereas the MAO‐B overexpression under glial fibrillary acidic protein (GFAP) promoter enhanced the levels of GFAP and GABA. Furthermore, we found that one of the by‐products of the MAO‐B action, H2O2, but not GABA, was sufficient and necessary for the hypertrophy of reactive astrocytes. Notably, we identified two potent pharmacological tools to attenuate scar‐forming astrogliosis—the recently developed reversible MAO‐B inhibitor, KDS2010, and an H2O2 scavenger, crisdesalazine (AAD‐2004). Our results implicate that inhibiting MAO‐B activity has dual beneficial effects in preventing astrogliosis and scar‐formation under brain injury, and that the MAO‐B/H2O2 pathway can be a useful therapeutic target with a high clinical potential.

Role of Hypothalamic Reactive Astrocytes in Diet-Induced Obesity

“…Astrocytes release numerous neuroactive molecules, including the classical inhibitory neurotransmitter GABA ( Garcia-Caceres et al, 2019 ; Lee et al, 2010 ; Yoon and Lee, 2014 ). Accumulating evidence suggest that elevated levels of GABA in reactive astrocytes act as a common molecular mechanism in various neuroinflammatory diseases ( Chun and Lee, 2018 ), such as Alzheimer’s disease ( Chun et al, 2020 ; Jo et al, 2014 ), Parkinson’s disease ( Heo et al, 2020 ), recovery after stroke ( Nam et al, 2020 ), stab-wound injury ( Chun et al, 2022 ), epileptic seizure ( Pandit et al, 2020 ) and inflammation-induced anxiety ( Shim et al, 2019 ). Consistently, it has been reported that extracellular GABA in mediobasal hypothalamus (ARC and VMH) is elevated in DIO mice ( Zhang et al, 2017 ).…”

Hypothalamic GABRA5-positive Neurons Control Obesity via Astrocytic GABA

“…Our study sheds a light on the missing link between the reactive astrogliosis and obesity, delineating the molecular and cellular mechanisms of how MAOB-dependent production of GABA leads to inhibition of energy expenditure and facilitation of fat storage. Elevated activity of MAOB and elevated levels of MAOB-dependent GABA have been highly implicated in the reactive astrocytes that are found in various neuroinflammatory diseases such as Alzheimer’s disease, Parkinson’s disease, stab-wound injury model and et cetera (Chun et al, 2021; Jo et al ., 2014; Nam et al, 2021; Pandit et al, 2020; Shim et al, 2019). The growing list of reports all point to the common molecular mechanism of how resting astrocytes transform into reactive astrocytes via the putrescine-degradation pathway involving MAOB under the conditions of aversive stimulations such as toxin challenges and viral infections, which usually accompany neuroinflammation (Chun et al ., 2018).…”

Inhibiting peripheral and central MAO-B ameliorates joint inflammation and cognitive impairment in rheumatoid arthritis

“…Monoamine oxidases (MAOs), including MAO-A and MAO-B, are enzymes that catalyze the oxidation of monoamines and are bound to the outer mitochondrial membrane in cells of several organs, such as the brain, liver, kidney, and the immune system 14,15 . Previous reports have suggested that MAO inhibitors can alleviate joint symptoms such as pain and stiffness in patients with RA, and there is growing evidence that MAO-B may be associated with systemic inflammation, especially neuroinflammation [16][17][18] . Moreover, joint inflammation in RA patients is associated with hydrogen peroxide (H 2 O 2 ) production, which might be mediated by MAO-B and mitigated by antioxidant administration, suggesting that MAO-B could be an effective therapeutic target for RA 17,19,20 .…”