title: 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.
authors.affiliation: Department of Biological Science and Technology, College of Life Science, China Medial University, Taichung, Taiwan.
authors.forename: Ling-Hsuan
authors.initials: LH
authors.lastname: Wu
authors.affiliation: Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chingju
authors.initials: C
authors.lastname: Lin
authors.affiliation: Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, Taiwan.
authors.forename: Hsiao-Yun
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Yu-Shu
authors.initials: YS
authors.lastname: Liu
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Caren Yu-Ju
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Cheng-Fang
authors.initials: CF
authors.lastname: Tsai
authors.affiliation: Department of Bioinformatics, Asia University, Taichung, Taiwan.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Chang
authors.affiliation: Department of Cell and Tissue Engineering, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Wei-Lan
authors.initials: WL
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, Taiwan. dahyuu@mail.cmu.edu.tw.|Department of Photonics and Communication Engineering, Asia University, Taichung, Taiwan. dahyuu@mail.cmu.edu.tw.
authors.forename: Dah-Yuu
authors.initials: DY
authors.lastname: Lu
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D044950:Flavanones / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D044950:Flavanones; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D051745:Protein Kinase C-delta; D000263:Adenylate Kinase; C005273:naringenin
keywords: CNS; Microglia; Naringenin; Neuroinflammation; SOCS-3