Abstract
As innate immune effector cells in the central nervous system (CNS), microglia not only are essential for the normal development of nervous system but also act on different neurological diseases, including Alzheimer's disease (AD), Huntington's disease (HD), and other neuroinflammatory diseases. Mogroside V (Mog), a natural plant active ingredient and isolated form of Momordica grosvenori, has been shown to possess anti-inflammatory action, but few studies were carried out to investigate the effects of Mog on neuroinflammation. This study aimed to investigate the role of Mog in lipopolysaccharide- (LPS-) induced neuroinflammation and neuronal damage, revealing the underlying mechanisms. Our data indicated that Mog significantly inhibited the LPS-induced production of proinflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-18, IL-6, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and high mobility group box 1 (HMGB1) in BV-2 cells. We found that Mog also suppressed toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), the phosphorylation of mitogen-activated protein kinases (MAPKs), adenosine 5′-monophosphate- (AMP-) activated protein kinase (AMPK), nuclear factor kappa-B (NF-κB), and protein kinase B (AKT). Moreover, Mog also enhanced the expression of γ-glutamyl cysteine synthetase catalytic subunit (GCLC), modifier subunit (GCLM), heme oxygenase-1 (HO-1), and quinine oxidoreductase 1 (NQO1) proteins, mostly depending on the nuclear translation of nuclear factor erythroid-2 related factor 2 (Nrf2). In contrast, pretreatment with inhibitors of AKT can suppress the phosphorylation of AMPK, Nrf2, and its downstream proteins expression. In summary, Mog might play a protective role against LPS-induced neurotoxicity by inhibiting the TLR4-MyD88 and activation of AMPK/AKT-Nrf2 signaling pathway.
Highlights
Neuroinflammation is recognized as a vital pathological process for various neurodegenerative diseases [1]
To determine the effect of Mogroside V (Mog) on the expression of inducible nitric oxide synthase (iNOS), COX-2, and high mobility group box 1 (HMGB1) proteins, BV-2 cells were treated with Mog (0, 6.25, 12.5, and 25 μM) for 2 h, followed by treatment with or without LPS (0.5 μg/mL) for 18 h. e data of western blot showed that the expressions of iNOS, COX-2, and HMGB1 were significantly increased by LPS treatment; these phenomena were reversed by 25 μM of Mog treatment and demonstrated a dose-dependent reduction (Figure 4)
Considering that the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway as a proinflammatory signaling pathway plays a key role in modulating the expression of many proinflammatory proteins, we examined whether Mog could reduce TLR4/MyD88 signaling pathway
Summary
Neuroinflammation is recognized as a vital pathological process for various neurodegenerative diseases [1]. LPS is a composition in the outer wall of Gram-negative bacteria cell wall As a ligand, it can be recognized by TLR4 [7], and it is highly expressed in microglia [8]. Via activation of TLR4, recruitment of MyD88, and activation of NF-κB, LPS-activated microglia lead to the increase of various inflammatory mediator expressions, including iNOS and COX-2, and proinflammatory cytokines, such as TNF-α, IL1β, IL-18, and IL-6 [9, 10]. Erefore, the aim of the present study was to explore the effects of Mog in LPS-induced microglia activation and further illustrate Mog-mediated signaling pathways of contributing to the beneficial effects and providing experimental evidence to develop new drug candidates against neuroinflammation Whether Mog can protect against neurocyte injury is still unknown. erefore, the aim of the present study was to explore the effects of Mog in LPS-induced microglia activation and further illustrate Mog-mediated signaling pathways of contributing to the beneficial effects and providing experimental evidence to develop new drug candidates against neuroinflammation
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