Naringenin Suppresses Neuroinflammatory Responses Through Inducing Suppressor of Cytokine Signaling 3 Expression

Abstract

Accumulating evidence suggests that neuroinflammation is closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. The hallmark of neuroinflammation is considered to be microglial activation in the central nervous system (CNS). Activated microglia release pro-inflammatory cytokines which cause neuroinflammation and progressive neuronal cell death. Therefore, inhibition of microglial activation is considered an important strategy in the development of neuroprotective strategy. Naringenin, a flavonoid found in citrus fruits and tomatoes, has been reported to have anti-oxidant, anti-cancer, and anti-inflammatory properties. However, the mechanism of its beneficial anti-inflammatory effects in the CNS is poorly understood. In this study, we demonstrated that naringenin inhibites the release of nitric oxide (NO), the expression of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), as well as pro-inflammatory cytokines in microglial cells. Treatment of naringenin also induced suppressors of cytokine signaling (SOCS)-3 expression in microglia. The SOCS-3 expression and anti-inflammatory effects of naringenin were found to be regulated by adenosine monophosphate-activated protein kinase α (AMPKα) and protein kinase C δ (PKCδ). Besides, naringenin exerted protective property against neurotoxicity caused by LPS-induced microglial activation. Our findings suggest that naringenin-inhibited iNOS and COX-2 expression is mediated by SOCS-3 activation through AMPKα and PKCδ signaling pathways. In a mouse model, naringenin also showed significant protective effects on microglial activation and improved motor coordination function as well. Therefore, naringenin that involves in anti-neuroinflammatory responses and neuroprotection might be a potential agent for treatment of inflammation-associated disorders.

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

“…Furthermore, activation of the microglia and the resulting neuroinflammation play a critical role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) [10]. Consequently, pharmacological modulation of pro-inflammatory mediators generated by the microglia during chronic inflammation and modulation of the signalling pathways responsible for their production is an important target in treating severe neuroinflammatory disorders.…”

“…NF-κB binds to the DNA and its transcriptional activity regulates several genes, which promote neuroinflammation. The p38 mitogenactivated protein kinase (p38 MAPK) signalling pathway also plays an important role in the expression and activity of pro-inflammatory cytokines in microglial cells [6][7][8].Excessive production of pro-inflammatory mediators generated during neuroinflammation can damage neighbouring neurons, and further activate the microglia, as well as other glia cells resulting in a self-perpetuating cycle [2,4,9].Furthermore, activation of the microglia and the resulting neuroinflammation play a critical role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) [10]. Consequently, pharmacological modulation of pro-inflammatory mediators generated by the microglia during chronic inflammation and modulation of the signalling pathways responsible for their production is an important target in treating severe neuroinflammatory disorders.…”

Naringenin improves learning and memory in an Alzheimer's disease rat model: Insights into the underlying mechanisms

“…Naringenin could inhibit neuroinflammation via cytokine signaling 3 and exert neuroprotection with potential benefit for treatment of inflammationassociated disorders like AD (Wu et al, 2015). Naringenin also exerts protective effects against lipopolysaccharide-induced microglial activation (Wu et al, 2015).…”

“…Naringenin could inhibit neuroinflammation via cytokine signaling 3 and exert neuroprotection with potential benefit for treatment of inflammationassociated disorders like AD (Wu et al, 2015). Naringenin also exerts protective effects against lipopolysaccharide-induced microglial activation (Wu et al, 2015). There are also reports indicating mitochondrial dysfunction with insufficient ATP synthesis and enhanced release of reactive oxygen species known generally as oxidative stress, neuroinflammation from 14 dysfunction of microglia and astrocytes, abnormal ApoE4 allele protein and aberrant Tau phosphorylation play key roles in pathophysiological changes in brains of AD patients (Weinstein et al, 2013).…”

Effect of heated naringenin on immunomodulatory properties and cellular antioxidant activity

“…Various pharmacological activities of NG, including antibacterial (Ng'uni et al 2015), antiviral (Lulu et al 2015;Meng et al 2015), antidiabetic (Bhattacharya et al 2014;Priscilla et al 2014), cardioprotective (Kara et al 2014), neuroprotective (Raza et al 2013), and nephroprotective effects (Hermenean et al 2013), were described. Previous studies have also reported that naringenin has antioxidative (Cavia-Saiz et al 2010;Kneževiae and Petlevski 2014), anti-inflammatory Wu et al 2015), and anticancer (Lin et al 2014) activities. The aim of this study was to investigate and to compare the immunomodulatory activity and cellular antioxidant potential of native naringenin (NG) and heated naringenin (hNG).…”