Neuroprotective effects of quercetin in a mouse model of brain ischemic/reperfusion injury via anti‑apoptotic mechanisms based on the Akt pathway

Lei,Xiaoming; Chao,Hailian; Zhang,Zhenni; Lv,Jianrui; Li,Siyuan; Wei,Haidong; Xue,Rongliang; Li,Fang; Li,Zongfang

doi:10.3892/mmr.2015.3857

Neuroprotective effects of quercetin in a mouse model of brain ischemic/reperfusion injury via anti‑apoptotic mechanisms based on the Akt pathway

Authors:
- Xiaoming Lei
- Hailian Chao
- Zhenni Zhang
- Jianrui Lv
- Siyuan Li
- Haidong Wei
- Rongliang Xue
- Fang Li
- Zongfang Li
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Affiliations: Department of Anesthesiology, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of General Surgery, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
Published online on: May 27, 2015 https://doi.org/10.3892/mmr.2015.3857
Pages: 3688-3696

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Abstract

The present study provided experimental evidence for the neuroprotective effects of quercetin using a rat model of global brain ischemic/reperfusion (I/R) injury. Pre‑treatment with quercetin (5 or 10 mg/kg orally (p.o.); once daily) induced a dose‑dependent reduction in I/R‑induced hippocampal neuron cell loss, with 10 mg/kg/day being the lowest dose that achieved maximal neuroprotection. Administration of 10 mg/kg quercetin over at least 3 days prior to I/R was required to improve the survival rate of I/R rats. Fluorescence‑assisted cell sorting, hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling indicated neuronal cell loss in the CA1 hippocampus. Rats that had undergone transient global cerebral ischemia for 15 min followed by 1 h of reperfusion exhibited a significant increase in reactive oxygen species (ROS) production in the hippocampus. The I/R‑induced ROS overproduction in the hippocampus at 1, 12 and 24 h following I/R was significantly decreased by quercetin pre‑treatment. Western blot analysis revealed that the neuroprotective effects of quercetin (5 and 10 mg/kg/day, p.o.) were associated with an upregulation of the I/R‑induced suppression of B‑cell lymphoma‑2 (Bcl‑2), Bcl extra large and survivin expression as well as phosphorylation of Bcl‑2‑associated death promoter. Furthermore, the neuroprotective effects of quercetin (5, 10 mg/kg/day) in the brain were associated with an upregulation of Akt signaling. These findings suggested that the inhibition of I/R‑induced brain injury by quercetin likely involves a transcriptional mechanism to enhance anti‑apoptotic signaling.

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1	Cherubini A, Ruggiero C, Morand C, et al: Dietary antioxidants as potential pharmacological agents for ischemic stroke. Curr Med Chem. 15:1236–1248. 2008. View Article : Google Scholar : PubMed/NCBI
2	Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM and Lines TC: A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol. 45:2179–2205. 2007. View Article : Google Scholar : PubMed/NCBI
3	Lee JC, Kim J, Park JK, Chung GH and Jang YS: The antioxidant, rather than prooxidant, activities of quercetin on normal cells: Quercetin protects mouse thymocytes from glucose oxidase-mediated apoptosis. Exp Cell Res. 291:386–397. 2003. View Article : Google Scholar : PubMed/NCBI
4	Lapi D, Vagnani S, Pignataro G, esposito E, Paterni M and Colantuoni A: Protective effects of Quercetin on Rat Pial micro-vascular changes during transient bilateral common carotid artery occlusion and reperfusion. Front Physiol. 3:322012.
5	Ghosh A, Sarkar S, Mandal AK and Das N: Neuroprotective role of nanoencapsulated quercetin in combating ischemia-reperfusion induced neuronal damage in young and aged rats. PLoS One. 8:e577352013. View Article : Google Scholar : PubMed/NCBI
6	Mattson MP, Duan W, Pedersen WA and Culmsee C: Neurodegenerative disorders and ischemic brain diseases. Apoptosis. 6:69–81. 2001. View Article : Google Scholar : PubMed/NCBI
7	Kowaltowski AJ, Castilho RF and Vercesi AE: Mitochondrial permeability transition and oxidative stress. FEBS Lett. 495:12–15. 2001. View Article : Google Scholar : PubMed/NCBI
8	Kuwana T, Mackey MR, Perkins G, et al: Bid, Bax and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell. 111:331–342. 2002. View Article : Google Scholar : PubMed/NCBI
9	Lei C, Deng J, Wang B, et al: Reactive oxygen species scavenger inhibits STAT3 activation after transient focal cerebral ischemia-reperfusion injury in rats. Anesth Analg. 113:153–159. 2011. View Article : Google Scholar : PubMed/NCBI
10	Priyadarsini RV and Nagini S: Quercetin suppresses cytochrome P450 mediated ROS generation and NF kappaB activation to inhibit the development of 7,12-dimethylbenz a anthracene (DMBA) induced hamster buccal pouch carcinomas. Free Radic Res. 46:41–49. 2012. View Article : Google Scholar
11	Yao RQ, Qi DS, Yu HL, Liu J, Yang LH and Wu XX: Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF-TrkB-PI3K/Akt signaling pathway. Neurochem Res. 37:2777–2786. 2012. View Article : Google Scholar : PubMed/NCBI
12	Mayo LD and Donner DB: A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA. 98:11598–11603. 2001. View Article : Google Scholar : PubMed/NCBI
13	Janelidze S, Hu BR, Siesjo P and Siesjo BK: Alterations of Akt1 (PKBalpha) and p70 (S6K) in transient focal ischemia. Neurobiol Dis. 8:147–154. 2001. View Article : Google Scholar : PubMed/NCBI
14	Shibata M, Yamawaki T, Sasaki T, et al: Upregulation of Akt phosphorylation at the early stage of middle cerebral artery occlusion in mice. Brain Res. 942:1–10. 2002. View Article : Google Scholar : PubMed/NCBI
15	Noshita N, Lewen A, Sugawara T and Chan PH: Evidence of phosphorylation of Akt and neuronal survival after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 21:1442–1450. 2001. View Article : Google Scholar : PubMed/NCBI
16	Xue RL, He JX, Wang N, Yao FZ, Lv JR and Wu G: Relationship between transmembrane signal transduction pathway and DNA repair and the mechanism after global cerebral ischemia-reperfusion in rats. Neurosci Bull. 25:115–121. 2009. View Article : Google Scholar : PubMed/NCBI
17	Hadley G, Papadakis M and Buchan AM: A method of inducing global cerebral ischemia. Methods Mol Biol. 1135:111–120. 2014. View Article : Google Scholar : PubMed/NCBI
18	Geocadin RG, Ghodadra R, Kimura T, et al: A novel quantitative EEG injury measure of global cerebral ischemia. Clin Neurophysiol. 111:1779–1787. 2000. View Article : Google Scholar : PubMed/NCBI
19	Vorhees CV and Williams MT: Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 1:848–858. 2006. View Article : Google Scholar
20	Stackman RW Jr, Lora JC and Williams SB: Directional responding of C57BL/6J mice in the Morris water maze is influenced by visual and vestibular cues and is dependent on the anterior thalamic nuclei. J Neurosci. 32:10211–10225. 2012. View Article : Google Scholar : PubMed/NCBI
21	Simao F, Matte A, Matte C, et al: Resveratrol prevents oxidative stress and inhibition of Na(+)K(+)-ATPase activity induced by transient global cerebral ischemia in rats. J Nutr Biochem. 22:921–928. 2011. View Article : Google Scholar : PubMed/NCBI
22	Johansson SE, Larsen SS, Povlsen GK and Edvinsson L: Early MEK1/2 inhibition after global cerebral ischemia in rats reduces brain damage and improves outcome by preventing delayed vasoconstrictor receptor upregulation. PLoS One. 9:e924172014. View Article : Google Scholar : PubMed/NCBI
23	Ahmad A, Khan MM, Hoda MN, et al: Quercetin protects against oxidative stress associated damages in a rat model of transient focal cerebral ischemia and reperfusion. Neurochem Res. 36:1360–1371. 2011. View Article : Google Scholar : PubMed/NCBI
24	Pandey AK, Hazari PP, Patnaik R and Mishra AK: The role of ASIC1a in neuroprotection elicited by quercetin in focal cerebral ischemia. Brain Res. 1383:289–299. 2011. View Article : Google Scholar : PubMed/NCBI
25	Rizk NN, Rafols JA and Dunbar JC: Cerebral ischemia-induced apoptosis and necrosis in normal and diabetic rats: effects of insulin and C-peptide. Brain Res. 1096:204–212. 2006. View Article : Google Scholar : PubMed/NCBI
26	Solaroglu I, Tsubokawa T, Cahill J and Zhang JH: Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat. Neuroscience. 143:965–974. 2006. View Article : Google Scholar : PubMed/NCBI
27	Yousuf S, Atif F, Ahmad M, et al: Resveratrol exerts its neuroprotective effect by modulating mitochondrial dysfunctions and associated cell death during cerebral ischemia. Brain Res. 1250:242–253. 2009. View Article : Google Scholar
28	Wang R, Li G, Wang W and Li H: Effect of compound preparation Tongqiao Jiannao capsules on neural cell apoptosis and Bcl-2 and Bax protein levels in a rat model of brain ischemia/reperfusion injury. Neural Regener Res. 3:871–874. 2008.
29	Babu PP, Yoshida Y, Su M, Segura M, Kawamura S and Yasui N: Immunohistochemical expression of Bcl-2, Bax and cytochrome c following focal cerebral ischemia and effect of hypothermia in rat. Neurosci Lett. 291:196–200. 2000. View Article : Google Scholar
30	Wang T, Gu J, Wu PF, et al: Protection by tetrahydroxystilbene glucoside against cerebral ischemia: involvement of JNK, SIRT1 and NF-kappaB pathways and inhibition of intracellular ROS/RNS generation. Free Radic Biol Med. 47:229–240. 2009. View Article : Google Scholar : PubMed/NCBI
31	Wu HW, Li HF, Wu XY, Zhao J and Guo J: Reactive oxygen species mediate ERK activation through different Raf-1-dependent signaling pathways following cerebral ischemia. Neurosci Lett. 432:83–87. 2008. View Article : Google Scholar : PubMed/NCBI
32	Wang Q, Sun AY, Simonyi A, et al: Ethanol preconditioning protects against ischemia/reperfusion-induced brain damage: Role of NADPH oxidase-derived ROS. Free Radic Biol Med. 43:1048–1060. 2007. View Article : Google Scholar : PubMed/NCBI
33	Liang JM, Xu HY, Zhang XJ, Li X, Zhang HB and Ge PF: Role of mitochondrial function in the protective effects of ischaemic postconditioning on ischaemia/reperfusion cerebral damage. J Int Med Res. 41:618–627. 2013. View Article : Google Scholar : PubMed/NCBI
34	Zhang L, Zhang ZG, Liu XS, Hozeska-Solgot A and Chopp M: The PI3K/Akt pathway mediates the neuroprotective effect of atorvastatin in extending thrombolytic therapy after embolic stroke in the rat. Arterioscler Thromb Vasc Biol. 27:2470–2475. 2007. View Article : Google Scholar : PubMed/NCBI
35	Endo H, Nito C, Kamada H, Nishi T and Chan PH: Activation of the Akt/GSK3beta signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats. J Cereb Blood Flow Metab. 26:1479–1489. 2006. View Article : Google Scholar : PubMed/NCBI
36	Fang XX, Jiang XL, Han XH, Peng YP and Qiu YH: Neuroprotection of interleukin-6 against NMDA-induced neurotoxicity is mediated by JAK/STAT3, MAPK/ERK and PI3K/AKT signaling pathways. Cell Mol Neurobiol. 33:241–251. 2013. View Article : Google Scholar
37	Gu R, Liu M, Wang Y, Zhou Y and He H: Angiopoietin-1 mRNA and Bcl-2 expression following estradiol treatment in ovariectomized rats with focal cerebral ischemia/reperfusion injury. Neural Regener Res. 4:780–785. 2009.
38	Kitagawa K: CREB and cAMP response element-mediated gene expression in the ischemic brain. FEBS J. 274:3210–3217. 2007. View Article : Google Scholar : PubMed/NCBI