The MAO Inhibitor Tranylcypromine Alters LPS- and Aβ-Mediated Neuroinflammatory Responses in Wild-type Mice and a Mouse Model of AD

Abstract

Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate LPS- and/or Aβ-induced neuroinflammation in the brain has not been well-studied. In the present study, we found that tranylcypromine selectively altered LPS-induced proinflammatory cytokine levels in BV2 microglial cells but not primary astrocytes. In addition, tranylcypromine modulated LPS-mediated TLR4/ERK/STAT3 signaling to alter neuroinflammatory responses in BV2 microglial cells. Importantly, tranylcypromine significantly reduced microglial activation as well as proinflammatory cytokine levels in LPS-injected wild-type mice. Moreover, injection of tranylcypromine in 5xFAD mice (a mouse model of AD) significantly decreased microglial activation but had smaller effects on astrocyte activation. Taken together, our results suggest that tranylcypromine can suppress LPS- and Aβ-induced neuroinflammatory responses in vitro and in vivo.

Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions

“…In the Alzheimer mouse model 5xFAD, this molecule significantly decreased microglial activation but had limited effects on astrocyte activation. In summary, this study indicates tranylcypromine as a potential therapeutic that can suppress LPS-and Aβ-induced neuroinflammatory responses both in vitro and in vivo [2].…”

A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury

“…Two isoforms of MAO encoded by MAOA and MAOB genes belong to the family of flavin-containing amine oxidoreductases, showing functional differences for their anatomic localization and major substrate ( Fisar, 2016 ; Shahid Nadeem et al, 2022 ). Previous studies have found that the inhibition of MAO activity can modulate LPS-induced microglial activation in vitro , suppressing the expression of pro-inflammatory factors ( Obuchowicz et al, 2006 ; Dhami et al, 2013 ; Park et al, 2020 ; Mariani et al, 2022 ). Rasagiline Mesylate (RM), a well-known irreversible MAO-B inhibitor, could suppress the expression of pro-inflammatory cytokines in LPS-treated BV2 cells ( Supplementary Figure S2 ).…”

Nilotinib modulates LPS-induced cognitive impairment and neuroinflammatory responses by regulating P38/STAT3 signaling

“…TLR subfamily 4 (TLR4) is activated by pathogenic molecules such as LPS. Several studies have reported that drugs that reduce proinflammatory cytokine levels in vitro and in vivo via TLR4-dependent signaling pathways hold potential for treating neuroinflammation-linked neurodegenerative diseases [ 20 , 21 , 36 , 37 ]. For instance, MAO inhibitor treatment significantly reduces the LPS-induced increase in IL-1β and IL-6 mRNA levels, and IL-6 but not IL-1β levels are partially dependent on TLR4 signaling in BV2 microglial cells [ 37 ].…”

“…Several studies have reported that drugs that reduce proinflammatory cytokine levels in vitro and in vivo via TLR4-dependent signaling pathways hold potential for treating neuroinflammation-linked neurodegenerative diseases [ 20 , 21 , 36 , 37 ]. For instance, MAO inhibitor treatment significantly reduces the LPS-induced increase in IL-1β and IL-6 mRNA levels, and IL-6 but not IL-1β levels are partially dependent on TLR4 signaling in BV2 microglial cells [ 37 ]. In addition, the VEGFR antagonist sorafenib and ATP-sensitive potassium channel blocker gliquidone reduce proinflammatory cytokine levels in BV2 microglia cells via TLR4-linked signaling pathways [ 21 , 36 ].…”