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

Hyunhee Park,Kyung-Min Han,Hyongjun Jeon,Jin-Hee Park,Hyunju Lee,Yu Gyung Kim,Young-Ho Lee,Hyang-Sook Hoe,Ji-Soo Lee,Seong Gak Jeon,Yuxi Lin,Yun Ha Jeong

doi:10.3390/cells9091982

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.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease associated with amyloid β (Aβ) and Tau pathologies, for which treatment options remain limited [1,2]
Tranylcypromine modulated Aβ-induced microglial activation in 5xFAD mice but had smaller effects on astrocyte activation. These results demonstrate that tranylcypromine affects LPS- and Aβ-induced neuroinflammatory responses in BV2 microglial cells, wild-type mice, and a mouse model of AD
MTT assays of BV2 microglial cells treated with vehicle (1% DMSO) or tranylcypromine (1, 5, 10, 25, or 50 μM) for 24 h showed that tranylcypromine did not exhibit BV2 cell cytotoxicity up to 50 μM

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease associated with amyloid β (Aβ) and Tau pathologies, for which treatment options remain limited [1,2]. Several recent studies have shown that neuroinflammation causes synaptic impairment and cognitive dysfunction, indicating that neuroinflammation is directly and/or indirectly involved in neurodegenerative diseases [3]. Aβ oligomers or fibrils interact with Toll-like receptors (TLRs; TLR4, TLR6, TLR9, and TLR2) expressed on microglial cells to promote the release of proinflammatory cytokines, including COX-2, IL-1β, and IL-6 [5]. These TLRs bind to lipopolysaccharide (LPS), leading to activation of proinflammatory cytokine genes via MyD88-dependent or MyD88-independent pathways to induce inflammatory responses [6]. Anti-inflammatory drugs may be useful to prevent/treat both neuroinflammation-related and neurogenerative diseases (e.g., AD)

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