Dextromethorphan Suppresses Lipopolysaccharide-Induced Epigenetic Histone Regulation in the Tumor Necrosis Factor-α Expression in Primary Rat Microglia.

Yung-Ning Yang,Pei-Ling Wu,San-Nan Yang,Yu-Chen S H Yang,Chun-Hwa Yang,Kuang-Che Kuo

doi:10.1155/2020/9694012

Abstract

The activation of microglial cells plays an important role in the cascade of events leading to inflammation-mediated neurodegenerative disorders. Precision therapeutics require that adjunctively feasible drugs be found to prevent microglial cell activation and prevent inflammation-mediated neuronal injury. Dextromethorphan (DM) has been reported to possess neuroprotective effects in lipopolysaccharide- (LPS-) stimulated animals; however, it remains unclear whether epigenetic regulatory mechanisms in microglial cells are involved in such DM-mediated neuroprotective effects. In this study, DM simultaneously suppressed LPS-induced activation of tumor necrosis factor- (TNF-) α expression and subsequent caspase-3 signaling in primary microglial cells associated with notable morphological changes. Furthermore, therapeutic action sites of DM involved differential enhanced trimethylation of H3K4 modifications in the promoter region of tnf-α gene locus in primary microglial cells. In summary, DM may exert neuroprotective and anti-inflammatory effects through differential epigenetic histone modifications of TNF-α expression in microglial cells and might therefore raise the possibility of providing an adjunctively beneficial role for a tentative therapeutic strategy in neurodegenerative diseases resulting from inflammation.

Highlights

The microglial cell serves as an important initiator of pathophysiological cascades leading to neuroinflammation through proinflammatory mediators within the central nervous system (CNS) [1]
Microglial cells can be activated by cytokines and/or chemokines and thereby release proinflammatory factors including interleukin-1β (IL-1β), interleukin-6 (IL-6), nitric oxide synthase, tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) [2, 3]
The immunohistochemical (IHC) morphology was evaluated in primary microglial cells

Summary

Introduction

The microglial cell serves as an important initiator of pathophysiological cascades leading to neuroinflammation through proinflammatory mediators within the central nervous system (CNS) [1]. Microglial cells can be activated by cytokines and/or chemokines and thereby release proinflammatory factors including interleukin-1β (IL-1β), interleukin-6 (IL-6), nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) [2, 3]. Bacterial LPS can trigger a cascade of biochemical events of the innate immune system and enhance an expression of microglia-derived proinflammatory factors, such as TNF-α, a crucial mediator of inflammation-mediated neurodegeneration [6]. It has long been known that the epigenetic regulatory mechanisms include DNA methylation, histone modification, and noncoding RNAs. The expression of TNF-α messenger RNA and protein was reported by epigenetic modifications of the TNF-α

Methods

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Discussion

Conclusion