Abstract
Neuroinflammation plays a central role in the pathophysiology of Alzheimer's disease (AD). Compounds that suppress neuroinflammation have been identified as potential therapeutic targets for AD. Rhinacanthin C (RC), a naphthoquinone ester found in Rhinacanthus nasutus Kurz (Acanthaceae), is currently proposed as an effective molecule against inflammation. However, the exact role of RC on neuroinflammation remains to be elucidated. In the present study, we investigated RC effect on modulating lipopolysaccharides (LPS), amyloid-β peptide (Aβ), or interferon-γ- (IFN-γ-) evoked pathological events in neurons and glia. Our findings demonstrated that RC prevented Aβ-induced toxicity in rat hippocampal neurons and attenuated LPS-activated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression, and NF-κB signaling in rat glia. Likewise, RC suppressed LPS-induced neuroinflammation by reducing NO production and iNOS, IL-1β, CCL-2, and CCL-5 mRNA levels in rat microglia. Further studies using BV-2 microglia revealed that RC inhibited LPS-, Aβ-, and IFN-γ-stimulated IL-6 and TNF-α secretion. Of note, NF-κB and ERK activation was abrogated by RC in BV-2 cell response to Aβ or IFN-γ. Moreover, RC protected neurons from Aβ-stimulated microglial conditioned media-dependent toxicity. Collectively, these data highlight the beneficial effects of RC on neuroprotection and support the therapeutic implications of RC to neuroinflammation-mediated conditions.
Highlights
Neuroinflammation is an inflammatory reaction within the central nervous system (CNS) and currently one of the major components contributing to Alzheimer’s disease (AD) pathology [1]
Approaches to target amyloid-β peptide (Aβ) via passive antibody or inhibition of γ-secretase therapy have not yet generated substantial clinical benefits, controlling the activation of microglia, and the resulting neuroinflammation has become a novel strategy for drug development for AD
Our results point to Rhinacanthin C (RC) exerting potent antineuroinflammatory and neuroprotective effects plausibly via NF-κB and ERK signaling pathways as depicted in Figure 10, which constitute a novel therapeutic measure to AD
Summary
Neuroinflammation is an inflammatory reaction within the central nervous system (CNS) and currently one of the major components contributing to Alzheimer’s disease (AD) pathology [1]. The features of neuroinflammation include infiltration of immune cells, activation of glial cells, and production of inflammatory mediators [2]. The resident phagocytes of the CNS, represent approximately 5–12% of the brain population [3]. Microglia patrol the brain for pathogens and support CNS homeostasis and plasticity with constant motility [4]. Upon sensing damage, such as protein aggregates, microglia respond by adopting a set of morphological and functional attributes, that is, “reactive” or “primed” [5]. Due to the neuronal damage in AD cannot be completely explained by the “amyloid cascade hypothesis” [7], more attention has been paid to the potential role of microglia in disease
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