N-Acetylcysteine Suppresses Microglial Inflammation and Induces Mortality Dose-Dependently via Tumor Necrosis Factor-α Signaling

Abstract

N-acetylcysteine (NAC) is an antioxidant that prevents tumor necrosis factor (TNF)-α-induced cell death, but it also acts as a pro-oxidant, promoting reactive oxygen species independent apoptosis. Although there is plausible preclinical evidence for the use of NAC in the treatment of psychiatric disorders, deleterious side effects are still of concern. Microglia, key innate immune cells in the brain, play an important role in inflammation in psychiatric disorders. This study aimed to investigate the beneficial and deleterious effects of NAC on microglia and stress-induced behavior abnormalities in mice, and its association with microglial TNF-α and nitric oxide (NO) production. The microglial cell line MG6 was stimulated by Escherichia coli lipopolysaccharide (LPS) using NAC at varying concentrations for 24 h. NAC inhibited LPS-induced TNF-α and NO synthesis, whereas high concentrations (≥30 mM) caused MG6 mortality. Intraperitoneal injections of NAC did not ameliorate stress-induced behavioral abnormalities in mice, but high-doses induced microglial mortality. Furthermore, NAC-induced mortality was alleviated in microglial TNF-α-deficient mice and human primary M2 microglia. Our findings provide ample evidence for the use of NAC as a modulating agent of inflammation in the brain. The risk of side effects from NAC on TNF-α remains unclear and merits further mechanistic investigations.

Lipid–polymer hybrid nanoparticles loaded with N-acetylcysteine for the modulation of neuroinflammatory biomarkers in human iPSC-derived PSEN2 (N141I) astrocytes as a model of Alzheimer's disease

“…23 On the other hand, free NAC (5 mM) tended to increase the relative expression of IL-6 (1.68), S100b (1.44), APP (1.24), and GFAP (1.77), implying that the activity of each gene could increase due to the concentration of NAC used. 62 This is in contrast to IL-1b, where it reduced to 0.63, as expected. It is important to mention that an increase in the level of messenger RNA (mRNA) results in an increase in its genetic activity, but there is no direct correlation between gene-to-protein or even mRNA-to-protein levels within the cell.…”

The interplay between oxidative stress and inflammation supports autistic-related behaviors in mice

“…6). The observation that NAC can suppress microglial inflammation via TNF signaling (39) indicates a possible mechanism of action occurring in the cerebellum of NAC-treated Cntnap2 −/− mice. Conversely, both frequency and branching of microglia cells were impaired in Cntnap2 +/+ animals after NAC administration (Fig.…”

Glial Markers of Suicidal Behavior in the Human Brain—A Systematic Review of Postmortem Studies

“…Microglial markers, including chemokine receptors such as C-X3-C motif chemokine receptor 1 (CX3CR1), may affect blood volume in the human brain [ 21 ]. Furthermore, we reported that the microglial response to acute and chronic stress influences cytokine production, such as interferon-alpha/beta/gamma (IFNα/β/γ), tumor necrosis factor (TNF-α), interleukin-1beta (IL-1β), IL-10, and transforming growth factor-beta 1 (TGF-β), and neurotransmitters [ 22 ] and behaviors in animal models [ 23 , 24 , 25 , 26 ]. Oligodendrocytes are myelinating cells of the CNS that account for about 5–10% of the total glia [ 27 ].…”