Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Inflammation Research
Published in: Inflammation Research 12/2020

01-12-2020 | Hypoxic-Ischemic Brain Injury | Original Research Paper

Quercetin alleviates neonatal hypoxic-ischemic brain injury by inhibiting microglia-derived oxidative stress and TLR4-mediated inflammation

Authors: Kai Le, Zhiping Song, Jie Deng, Xin Peng, Jun Zhang, Liang Wang, Lu Zhou, Haidi Bi, Zhengyu Liao, Zhen Feng

Published in: Inflammation Research | Issue 12/2020

Login to get access

Abstract

Objective and design

Microglia stimulated by oxygen glucose deprivation (OGD) were treated with quercetin to investigate the effect on oxidative stress and the inflammatory response and to explore whether toll-like receptor 4 (TLR4) signaling was involved. In addition, the effect of quercetin on the neurological functions of neonatal mice with hypoxic-ischemic brain injury (HIBI) was examined.

Materials and subjects

Mouse BV2 microglial cells and postnatal day 7 neonatal mice were used.

Treatment

A predetermined concentration of quercetin was used in cell experiments. Quercetin was injected i.p. (50 mg/kg) at three time points after HI insult: 0, 24, and 48 h.

Methods

Cell viability assay, Western blotting, qRT-RCR, ELISA, HIBI model construction and behavioral tests.

Results

This study first showed that quercetin protected BV2 cells from OGD-induced damage and reversed the changes in microglial oxidative stress-related molecules. Second, quercetin inhibited OGD-induced expression of inflammatory factors in BV2 cells and suppressed TLR4/MyD88/NF-κB signaling. Finally, quercetin was disclosed to be effective in mitigating cerebral infarct volume and cognitive and motor function deficits in HIBI mice.

Conclusion

These results suggest that the neuroprotective effect of quercetin in HIBI mice is partially due to the inhibition of oxidative stress and TLR4-mediated inflammatory responses in activated microglia.
Literature
1.
Yildiz EP, Ekici B, Tatli B. Neonatal hypoxic ischemic encephalopathy: an update on disease pathogenesis and treatment. Expert Rev Neurother. 2017;17:449–59.PubMedCrossRef
2.
Finder M, Boylan GB, Twomey D, Ahearne C, Murray DM, Hallberg B. Two-year neurodevelopmental outcomes after mild hypoxic ischemic encephalopathy in the era of therapeutic hypothermia. JAMA Pediatr. 2020;174(1):48–55.PubMedCrossRef
3.
Azzopardi D, Strohm B, Marlow N, Brocklehurst P, Deierl A, Eddama O, et al. Effects of hypothermia for perinatal asphyxia on childhood outcomes. New Engl J Med. 2014;371:140–9.PubMedCrossRef
4.
Torres-Cuevas I, Corral-Debrinski M, Gressens P. Brain oxidative damage in murine models of neonatal hypoxia/ischemia and reoxygenation. Free Radical Biol Med. 2019;142:3–15.CrossRef
5.
6.
Le K, Wu S, Chibaatar E, Ali AI, Guo Y. Alarmin HMGB1 plays a detrimental role in hippocampal dysfunction caused by hypoxia-ischemia insult in neonatal mice: evidence from the application of the HMGB1 inhibitor glycyrrhizin. ACS Chem Neurosci. 2020;11:979–93.PubMedCrossRef
7.
Le K, Chibaatar Daliv E, Wu S, Qian F, Ali AI, Yu D, et al. SIRT1-regulated HMGB1 release is partially involved in TLR4 signal transduction: a possible anti-neuroinflammatory mechanism of resveratrol in neonatal hypoxic-ischemic brain injury. Int Immunopharmacol. 2019;75:105779.PubMedCrossRef
8.
Umekawa T, Osman AM, Han W, Ikeda T, Blomgren K. Resident microglia, rather than blood-derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia-ischemia. Glia. 2015;63:2220–30.PubMedPubMedCentralCrossRef
9.
Thornton C, Baburamani AA, Kichev A, Hagberg H. Oxidative stress and endoplasmic reticulum (ER) stress in the development of neonatal hypoxic-ischaemic brain injury. Biochem Soc Trans. 2017;45:1067–76.PubMedPubMedCentralCrossRef
10.
Li C, Bian Y, Feng Y, Tang F, Wang L, Hoi MPM, et al. Neuroprotective effects of BHDPC, a novel neuroprotectant, on experimental stroke by modulating microglia polarization. ACS Chem Neurosci. 2019;10:2434–49.PubMedCrossRef
11.
Velagapudi R, Jamshaid F, Lepiarz I, Katola FO, Hemming K, Olajide OA. The tiliroside derivative, 3-O-[(E)-(2-oxo-4-(p-tolyl) but-3-en-1-yl] kaempferol produced inhibition of neuroinflammation and activation of AMPK and Nrf2/HO-1 pathways in BV-2 microglia. Int Immunopharmacol. 2019;77:105951.PubMedCrossRef
12.
Zalewska T, Jaworska J, Ziemka-Nalecz M. Current and experimental pharmacological approaches in neonatal hypoxic- ischemic encephalopathy. Curr Pharm Des. 2015;21:1433–9.PubMedCrossRef
13.
de Boer VC, Dihal AA, van der Woude H, Arts IC, Wolffram S, Alink GM, et al. Tissue distribution of quercetin in rats and pigs. J Nutr. 2005;135:1718–25.PubMedCrossRef
14.
da Silveira de Mattos B, Soares MSP, Spohr L, Pedra NS, Teixeira FC, de Souza AA, et al. Quercetin prevents alterations of behavioral parameters, delta-aminolevulinic dehydratase activity and oxidative damage in brain of rats in a prenatal model of autism. Int J Dev Neurosci. 2020;80(4):287–302.CrossRef
15.
Chakraborty J, Singh R, Dutta D, Naskar A, Rajamma U, Mohanakumar KP. Quercetin improves behavioral deficiencies, restores astrocytes and microglia, and reduces serotonin metabolism in 3-nitropropionic acid-induced rat model of Huntington’s disease. CNS Neurosci Ther. 2014;20:10–9.PubMedCrossRef
16.
Lee JK, Kwak HJ, Piao MS, Jang JW, Kim SH, Kim HS. Quercetin reduces the elevated matrix metalloproteinases-9 level and improves functional outcome after cerebral focal ischemia in rats. Acta Neurochir. 2011;153:1321–9 (discussion 1329).PubMedCrossRef
17.
Qu X, Qi D, Dong F, Wang B, Guo R, Luo M, et al. Quercetin improves hypoxia-ischemia induced cognitive deficits via promoting remyelination in neonatal rat. Brain Res. 2014;1553:31–40.PubMedCrossRef
18.
Wu M, Liu F, Guo Q. Quercetin attenuates hypoxia-ischemia induced brain injury in neonatal rats by inhibiting TLR4/NF-κB signaling pathway. Int Immunopharmacol. 2019;74:105704.PubMedCrossRef
19.
Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. P Natl Acad Sci USA. 2003;100:8514–9.CrossRef
20.
National Research Council Committee for the Update of the Guide for the C, Use of Laboratory A. The National Academies Collection: Reports funded by National Institutes of Health. In: th, editor. Guide for the Care and Use of Laboratory Animals. Washington (DC): National Academies Press (US)National Academy of Sciences., 2011.
21.
Yao D, Zhang WR, He X, Wang JH, Jiang KW, Zhao ZY. Establishment and identification of a hypoxia-ischemia brain damage model in neonatal rats. Biomed Rep. 2016;4:437–43.PubMedPubMedCentralCrossRef
22.
Sun HS, Xu B, Chen W, Xiao A, Turlova E, Alibraham A, et al. Neuronal K(ATP) channels mediate hypoxic preconditioning and reduce subsequent neonatal hypoxic-ischemic brain injury. Exp Neurol. 2015;263:161–71.PubMedCrossRef
23.
24.
Amanzadeh E, Esmaeili A, Rahgozar S, Nourbakhshnia M. Application of quercetin in neurological disorders: from nutrition to nanomedicine. Rev Neurosci. 2019;30:555–72.PubMedCrossRef
25.
Ahmad A, Khan MM, Hoda MN, Raza SS, Khan MB, Javed H, et al. Quercetin protects against oxidative stress associated damages in a rat model of transient focal cerebral ischemia and reperfusion. Neurochem Res. 2011;36:1360–71.PubMedCrossRef
26.
27.
Panfoli I, Candiano G, Malova M, De Angelis L, Cardiello V, Buonocore G, et al. Oxidative stress as a primary risk factor for brain damage in preterm Newborns. Front Pediatrics. 2018;6:369.CrossRef
28.
Sharma A, Liaw K, Sharma R, Zhang Z, Kannan S, Kannan RM. Targeting mitochondrial dysfunction and oxidative stress in activated microglia using dendrimer-based therapeutics. Theranostics. 2018;8:5529–47.PubMedPubMedCentralCrossRef
29.
Kim KI, Chung YC, Jin BK. Norfluoxetine prevents degeneration of dopamine neurons by inhibiting microglia-derived oxidative stress in an MPTP mouse model of Parkinson’s disease. Mediators Inflamm. 2018;2018:4591289.PubMedPubMedCentral
30.
Xu X, Zhang L, Ye X, Hao Q, Zhang T, Cui G, et al. Nrf2/ARE pathway inhibits ROS-induced NLRP3 inflammasome activation in BV2 cells after cerebral ischemia reperfusion. Inflamm Res. 2018;67:57–655.PubMedCrossRef
31.
Mallard C, Davidson JO, Tan S, Green CR, Bennet L, Robertson NJ, et al. Astrocytes and microglia in acute cerebral injury underlying cerebral palsy associated with preterm birth. Pediatr Res. 2014;75:234–40.PubMedCrossRef
32.
33.
Mrvova N, Skandik M, Kuniakova M, Rackova L. Modulation of BV-2 microglia functions by novel quercetin pivaloyl ester. Neurochem Int. 2015;90:246–54.PubMedCrossRef
34.
Kang CH, Choi YH, Moon SK, Kim WJ, Kim GY. Quercetin inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-κB pathway and activating the Nrf2-dependent HO-1 pathway. Int Immunopharmacol. 2013;17:808–13.PubMedCrossRef
35.
Zhang P, Cheng G, Chen L, Zhou W, Sun J. Cerebral hypoxia-ischemia increases Toll-like receptor 2 and 4 expression in the hippocampus of neonatal rats. Brain Develop. 2015;37:747–52.CrossRef
36.
Tang Z, Cheng SW, Sun YY, Zhang YQ, Xiang XY, Ouyang ZC, et al. Early TLR4 inhibition reduces hippocampal injury at puberty in a rat model of neonatal hypoxic-ischemic brain damage via regulation of neuroimmunity and synaptic plasticity. Exp Neurol. 2019;321:113039.PubMedCrossRef
37.
38.
Xia W, Luo P, Hua P, Ding P, Li C, Xu J, et al. Discovery of a new pterocarpan-type antineuroinflammatory compound from Sophora tonkinensis through suppression of the TLR4/NFkappaB/MAPK signaling pathway with PU.1 as a potential target. ACS Chem Neurosci. 2019;10:295–303.PubMedCrossRef
39.
Wang X, Northcutt AL, Cochran TA, Zhang X, Fabisiak TJ, Haas ME, et al. Methamphetamine activates Toll-like receptor 4 to induce central immune signaling within the ventral tegmental area and contributes to extracellular dopamine increase in the nucleus accumbens shell. ACS Chem Neurosci. 2019;10:3622–34.PubMedCrossRef
40.
Trotta T, Porro C, Calvello R, Panaro MA. Biological role of Toll-like receptor-4 in the brain. J Neuroimmunol. 2014;268:1–12.PubMedCrossRef
41.
Hakimizadeh E, Kazemi Arababadi M, Shamsizadeh A, Roohbakhsh A, Allahtavakoli M. The possible role of Toll-like receptor 4 in the pathology of stroke. NeuroImmunoModulation. 2016;23:131–6.PubMedCrossRef
42.
Cao CX, Yang QW, Lv FL, Cui J, Fu HB, Wang JZ. Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. Biochem Biophys Res Commun. 2007;353:509–14.PubMedCrossRef
43.
Wang D, Zhao J, Li S, Shen G, Hu S. Quercetin attenuates domoic acid-induced cognitive deficits in mice. Nutr Neurosci. 2018;21:123–31.PubMedCrossRef
44.
Li YL, Guo H, Zhao YQ, Li AF, Ren YQ, Zhang JW. Quercetin protects neuronal cells from oxidative stress and cognitive degradation induced by amyloid beta-peptide treatment. Mol Med Reports. 2017;16:1573–7.CrossRef
45.
Paula PC, Angelica Maria SG, Luis CH, Gloria Patricia CG. preventive effect of quercetin in a triple transgenic Alzheimer’s disease Mice Model. Molecules (Basel, Switzerland). 2019;24:2287.CrossRef
46.
Asehnoune K, Strassheim D, Mitra S, Kim JY, Abraham E. Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-κB. J Immunol. 2004;172:2522–9.PubMedCrossRef
Metadata
Title
Quercetin alleviates neonatal hypoxic-ischemic brain injury by inhibiting microglia-derived oxidative stress and TLR4-mediated inflammation
Authors
Kai Le
Zhiping Song
Jie Deng
Xin Peng
Jun Zhang
Liang Wang
Lu Zhou
Haidi Bi
Zhengyu Liao
Zhen Feng
Publication date
01-12-2020
Publisher
Springer International Publishing
Published in
Inflammation Research / Issue 12/2020
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-020-01402-5

Other articles of this Issue 12/2020

Inflammation Research 12/2020 Go to the issue

Original Research Paper

Macrophage-derived Wnt signaling increases endothelial permeability during skeletal muscle injury

Original Research Paper

Roflumilast prevents lymphotoxin α (TNF-β)-induced inflammation activation and degradation of type 2 collagen in chondrocytes

Original Research Paper

IL-33 enhances macrophage release of IL-1β and promotes pain and inflammation in gouty arthritis

Review

The coagulopathy, endotheliopathy, and vasculitis of COVID-19

Original Research Paper

TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy

Original Research Paper

Biochanin A attenuates zymosan-induced arthritis in mice similarly to 17-β estradiol: an alternative to hormone replacement therapy?

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits