Amentoflavone Exerts Anti-Neuroinflammatory Effects by Inhibiting TLR4/MyD88/NF-κB and Activating Nrf2/HO-1 Pathway in Lipopolysaccharide-Induced BV2 Microglia

Background Amentoflavone, a natural biflavone, exerts anti-inflammation, antioxidation, and antiapoptosis effects on many diseases. However, the mechanism of amentoflavone on neuroinflammation-related diseases has not been comprehensively examined clearly. Methods BV2 microglial cells were treated with amentoflavone (10 μM), followed by lipopolysaccharide (LPS). Microglial activation and migration ability and the expression of proinflammatory cytokines and other signaling proteins were determined using immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay, and wound-healing assays. Results Amentoflavone restored LPS-induced microglia activation, migration, and inflammation response which depends on regulating toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-κB) pathway. In addition, amentoflavone also enhanced nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) levels in LPS-treated BV2 microglial cells. Conclusions Amentoflavone ameliorated LPS-induced neuroinflammatory response and oxidative stress in BV2 microglia. These data provide new insight into the mechanism of amentoflavone in the treatment of neuroinflammation-related diseases. Therefore, amentoflavone may be a potential therapeutic option for neurological disorders.

[1]  Zhihe Liu,et al.  Insights Into Amentoflavone: A Natural Multifunctional Biflavonoid , 2021, Frontiers in Pharmacology.

[2]  P. Castillo,et al.  Altered synaptic connectivity and brain function in mice lacking microglial adapter protein Iba1 , 2021, Proceedings of the National Academy of Sciences.

[3]  P. Poma NF-κB and Disease , 2020, International journal of molecular sciences.

[4]  W. Cho,et al.  Integrin α1 promotes tumorigenicity and progressive capacity of colorectal cancer , 2020, International journal of biological sciences.

[5]  Kunmei Liu,et al.  [Amentoflavone inhibits inflammation of mouse BV-2 microglia cells induced by lipopolysaccharide]. , 2020, Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology.

[6]  Feng Wang,et al.  Amentoflavone Affects Epileptogenesis and Exerts Neuroprotective Effects by Inhibiting NLRP3 Inflammasome , 2019, Front. Pharmacol..

[7]  Farzane Sivandzade,et al.  Cerebrovascular and Neurological Disorders: Protective Role of NRF2 , 2019, International journal of molecular sciences.

[8]  A. Vezzani,et al.  Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy , 2019, Nature Reviews Neurology.

[9]  Ling Zhu,et al.  Interleukin-1 causes CNS inflammatory cytokine expression via endothelia-microglia bi-cellular signaling , 2019, Brain, Behavior, and Immunity.

[10]  H. Sha,et al.  The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases , 2019, Aging and disease.

[11]  Beth Stevens,et al.  Immune Signaling in Neurodegeneration. , 2019, Immunity.

[12]  K. Shannon,et al.  Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice , 2018, Gut.

[13]  Xuming Deng,et al.  Amentoflavone Ameliorates Streptococcus suis-Induced Infection In Vitro and In Vivo , 2018, Applied and Environmental Microbiology.

[14]  Yong Wang,et al.  Disparate roles of CXCR3A and CXCR3B in regulating progressive properties of colorectal cancer cells , 2018, Molecular carcinogenesis.

[15]  Ignacio Lizasoain,et al.  TLR4-Binding DNA Aptamers Show a Protective Effect against Acute Stroke in Animal Models. , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  R. Donato,et al.  Nrf2-Keap1 signaling in oxidative and reductive stress. , 2018, Biochimica et biophysica acta. Molecular cell research.

[17]  Ningning Zhao,et al.  Amentoflavone Ameliorates Aβ1–42-Induced Memory Deficits and Oxidative Stress in Cellular and Rat Model , 2018, Neurochemical Research.

[18]  Ming Liu,et al.  Upregulation of HMGB1-TLR4 inflammatory pathway in focal cortical dysplasia type II , 2018, Journal of Neuroinflammation.

[19]  W. Ding,et al.  TLR4 signal ablation attenuated neurological deficits by regulating microglial M1/M2 phenotype after traumatic brain injury in mice , 2017, Journal of Neuroimmunology.

[20]  R. Thangavel,et al.  Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration , 2017, Front. Cell. Neurosci..

[21]  W. Löscher,et al.  Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy , 2017, Epilepsia.

[22]  M. Pirmohamed,et al.  Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy , 2017, The Journal of clinical investigation.

[23]  Dean Y. Li,et al.  Endothelial TLR4 and the microbiome drive cerebral cavernous malformations , 2017, Nature.

[24]  Hailian Shi,et al.  Amentoflavone protects dopaminergic neurons in MPTP‐induced Parkinson's disease model mice through PI3K/Akt and ERK signaling pathways , 2017, Toxicology and applied pharmacology.

[25]  H. Hartung,et al.  Dimethyl fumarate accelerates peripheral nerve regeneration via activation of the anti-inflammatory and cytoprotective Nrf2/HO-1 signaling pathway , 2017, Acta Neuropathologica.

[26]  Jing-Shan Shi,et al.  TLR4 is a link between diabetes and Alzheimer’s disease , 2017, Behavioural Brain Research.

[27]  Qing-Wu Yang,et al.  Toll-Like Receptor 4/MyD88–Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage , 2016, Circulation.

[28]  Andrea Gallo,et al.  Parkinson's disease: Autoimmunity and neuroinflammation. , 2016, Autoimmunity reviews.

[29]  Paul Edison,et al.  Neuroinflammation in Alzheimer's disease: Current evidence and future directions , 2016, Alzheimer's & Dementia.

[30]  K. Nakayama,et al.  Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription , 2016, Nature Communications.

[31]  M. Conconi,et al.  Ligand engagement of Toll-like receptors regulates their expression in cortical microglia and astrocytes , 2015, Journal of Neuroinflammation.

[32]  Feng Wang,et al.  Amentoflavone protects hippocampal neurons: anti-inflammatory, antioxidative, and antiapoptotic effects , 2015, Neural regeneration research.

[33]  L. Benowitz,et al.  NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage. , 2015, The Journal of clinical investigation.

[34]  Q. Lu,et al.  TLR2 and TLR4 in Autoimmune Diseases: a Comprehensive Review , 2014, Clinical Reviews in Allergy & Immunology.

[35]  C. Porro,et al.  Biological role of Toll-like receptor-4 in the brain , 2014, Journal of Neuroimmunology.

[36]  K. Sakthivel,et al.  Amentoflavone inhibits iNOS, COX-2 expression and modulates cytokine profile, NF-κB signal transduction pathways in rats with ulcerative colitis. , 2013, International immunopharmacology.

[37]  M. Falip,et al.  Causes of CNS Inflammation and Potential Targets for Anticonvulsants , 2013, CNS Drugs.

[38]  P. Piccini,et al.  Imaging of Microglia in Patients with Neurodegenerative Disorders , 2012, Front. Pharmacol..

[39]  M. Karin,et al.  NF‐κB and the link between inflammation and cancer , 2012, Immunological reviews.

[40]  P. Mcgeer,et al.  History of Innate Immunity in Neurodegenerative Disorders , 2011, Front. Pharmacol..

[41]  E. Aronica,et al.  Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures , 2010, Nature Medicine.

[42]  W. Yeh,et al.  LPS/TLR4 signal transduction pathway. , 2008, Cytokine.