Curcumin exerts protective effects against hypoxia‑reoxygenation injury via the enhancement of apurinic/apyrimidinic endonuclease 1 in SH‑SY5Y cells: Involvement of the PI3K/AKT pathway

Wu,Lei; Jiang,Cao; Kang,Ying; Dai,Yaji; Fang,Wei; Huang,Peng

doi:10.3892/ijmm.2020.4483

Curcumin exerts protective effects against hypoxia‑reoxygenation injury via the enhancement of apurinic/apyrimidinic endonuclease 1 in SH‑SY5Y cells: Involvement of the PI3K/AKT pathway

Authors:
- Lei Wu
- Cao Jiang
- Ying Kang
- Yaji Dai
- Wei Fang
- Peng Huang
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Affiliations: Department of Neurology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China, Department of Neurology, Deqing County People's Hospital, Huzhou, Zhejiang 313200, P.R. China, Department of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei, Anhui 230012, P.R. China
Published online on: February 4, 2020 https://doi.org/10.3892/ijmm.2020.4483
Pages: 993-1004
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Curcumin, a polyphenolic compound extracted from the plant Curcuma longa, has been reported to exert neuroprotective effects against cerebral ischemia reperfusion (I/R) injury. However, the mechanisms underlying these effects remain to be fully elucidated. Emerging evidence indicated that apurinic/apyrimidinic endonuclease 1 (APE1), a multifunctional enzyme, participates in neuronal survival against I/R injury. Therefore, the aim of the present study was to investigate whether curcumin alleviates oxygen‑glucose deprivation/reperfusion (OGD/R)‑induced SH‑SY5Y cell injury, which serves as an in vitro model of cerebral I/R injury, by regulating APE1. The results revealed that curcumin increased cell viability, decreased LDH activity, reduced apoptosis and caspase‑3 activity, downregulated the pro‑apoptotic protein Bax expression and upregulated the anti‑apoptotic protein Bcl‑2 expression in SH‑SY5Y cells subjected to OGD/R. Simultaneously, curcumin eliminated the OGD/R‑induced decreases in APE1 protein and mRNA expression, as well as 8‑hydroxy‑2'‑deoxyguanosine (8‑OHdG) level and AP sites in SH‑SY5Y cells. However, APE1 knockdown by siRNA transfection markedly abrogated the protective effects of curcumin against OGD/R‑induced cytotoxicity, apoptosis and oxidative stress, as illustrated by the decreases in reactive oxygen species production and NADPH oxidase 2 expression, and the increase in superoxide dismutase activity and glutathione levels in SH‑SY5Y cells. Furthermore, curcumin mitigated the OGD/R‑induced activation of phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) signaling pathway. Treatment with LY294002, an inhibitor of PI3K/AKT pathway activity, attenuated the protective effects of curcumin on cytotoxicity and apoptosis, and reversed the curcumin‑induced upregulation of APE1 protein expression in SH‑SY5Y cells subjected to OGD/R. Taken together, these results demonstrated that curcumin protects SH‑SY5Y cells against OGD/R injury by inhibiting apoptosis and oxidative stress, and via enhancing the APE1 level and activity, promoting PI3K/AKT pathway activation.

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1	Hausenloy DJ and Yellon DM: Ischaemic conditioning and reperfusion injury. Nat Rev Cardiol. 13:193–209. 2016. View Article : Google Scholar : PubMed/NCBI
2	Lee RHC, Lee MHH, Wu CYC, Couto E, Silva A, Possoit HE, Hsieh TH, Minagar A and Lin HW: Cerebral ischemia and neuroregeneration. Neural Regen Res. 13:373–385. 2018. View Article : Google Scholar : PubMed/NCBI
3	Millar LJ, Shi L, Hoerder-Suabedissen A and Molnar Z: Neonatal hypoxia ischaemia: Mechanisms, models, and therapeutic challenges. Front Cell Neurosci. 11:782017. View Article : Google Scholar : PubMed/NCBI
4	Sun MS, Jin H, Sun X, Huang S, Zhang FL, Guo ZN and Yang Y: Free radical damage in ischemia-reperfusion injury: An obstacle in acute ischemic stroke after revascularization therapy. Oxid Med Cell Longev. 2018:38049792018. View Article : Google Scholar : PubMed/NCBI
5	Thornton C, Leaw B, Mallard C, Nair S, Jinnai M and Hagberg H: Cell death in the developing brain after hypoxia-ischemia. Front Cell Neurosci. 11:2482017. View Article : Google Scholar : PubMed/NCBI
6	Leiva-Salinas C, Patrie JT, Xin W, Michel P, Jovin T and Wintermark M: Prediction of early arterial recanalization and tissue fate in the selection of patients with the greatest potential to benefit from intravenous tissue-type plasminogen activator. Stroke. 47:397–403. 2016. View Article : Google Scholar
7	Rother J, Ford GA and Thijs VN: Thrombolytics in acute ischaemic stroke: Historical perspective and future opportunities. Cerebrovasc Dis. 35:313–319. 2013. View Article : Google Scholar : PubMed/NCBI
8	Cheng CY and Lee YC: Anti-inflammatory effects of traditional chinese medicines against ischemic injury in in vivo models of cerebral ischemia. Evid Based Complement Alternat Med. 2016:57394342016. View Article : Google Scholar : PubMed/NCBI
9	Feigin VL: Herbal medicine in stroke: Does it have a future? Stroke. 38:1734–1736. 2007. View Article : Google Scholar : PubMed/NCBI
10	Ip FC, Zhao YM, Chan KW, Cheng EY, Tong EP, Chandrashekar O, Fu GM, Zhao ZZ and Ip NY: Neuroprotective effect of a novel Chinese herbal decoction on cultured neurons and cerebral ischemic rats. BMC Complement Altern Med. 16:4372016. View Article : Google Scholar : PubMed/NCBI
11	Lestari ML and Indrayanto G: Curcumin. Profiles Drug Subst Excip Relat Methodol. 39:113–204. 2014. View Article : Google Scholar : PubMed/NCBI
12	Maiti P and Dunbar GL: Use of curcumin, a natural polyphenol for targeting molecular pathways in treating age-related neurodegenerative diseases. Int J Mol Sci. 19:E16372018. View Article : Google Scholar : PubMed/NCBI
13	Rahmani AH, Alsahli MA, Aly SM, Khan MA and Aldebasi YH: Role of curcumin in disease prevention and treatment. Adv Biomed Res. 7:382018. View Article : Google Scholar : PubMed/NCBI
14	Lee WH, Loo CY, Bebawy M, Luk F, Mason RS and Rohanizadeh R: Curcumin and its derivatives: Their application in neuropharmacology and neuroscience in the 21st century. Curr Neuropharmacol. 11:338–378. 2013. View Article : Google Scholar :
15	Wicha P, Tocharus J, Janyou A, Jittiwat J, Changtam C, Suksamrarn A and Tocharus C: Hexahydrocurcumin protects against cerebral ischemia/reperfusion injury, attenuates inflammation, and improves antioxidant defenses in a rat stroke model. PLoS One. 12:e01892112017. View Article : Google Scholar : PubMed/NCBI
16	Wu JX, Zhang LY, Chen YL, Yu SS, Zhao Y and Zhao J: Curcumin pretreatment and post-treatment both improve the antioxidative ability of neurons with oxygen-glucose deprivation. Neural Regen Res. 10:481–489. 2015. View Article : Google Scholar : PubMed/NCBI
17	Xanthoudakis S and Curran T: Identification and characterization of Ref-1, a nuclear protein that facilitates AP-1 DNA-binding activity. EMBO J. 11:653–665. 1992. View Article : Google Scholar : PubMed/NCBI
18	Lan J, Li W, Zhang F, Sun FY, Nagayama T, O'Horo C and Chen J: Inducible repair of oxidative DNA lesions in the rat brain after transient focal ischemia and reperfusion. J Cereb Blood Flow Metab. 23:1324–1339. 2003. View Article : Google Scholar : PubMed/NCBI
19	Leak RK, Li P, Zhang F, Sulaiman HH, Weng Z, Wang G, Stetler RA, Shi Y, Cao G, Gao Y and Chen J: Apurinic/apyrimidinic endonuclease 1 upregulation reduces oxidative DNA damage and protects hippocampal neurons from ischemic injury. Antioxid Redox Signal. 22:135–148. 2015. View Article : Google Scholar :
20	Kim HW, Cho KJ, Lee BI, Kim HJ and Kim GW: Post-ischemic administration of peptide with apurinic/apyrimidinic endonu-clease activity inhibits induction of cell death after focal cerebral ischemia/reperfusion in mice. Neurosci Lett. 460:166–169. 2009. View Article : Google Scholar : PubMed/NCBI
21	Kim HW, Cho KJ, Park SC, Kim HJ and Kim GW: The adenoviral vector-mediated increase in apurinic/apyrimidinic endonuclease inhibits the induction of neuronal cell death after transient ischemic stroke in mice. Brain Res. 1274:1–10. 2009. View Article : Google Scholar : PubMed/NCBI
22	Jia JY, Tan ZG, Liu M and Jiang YG: Apurinic/apyrimidinic endonuclease 1 (APE1) contributes to resveratrol-induced neuroprotection against oxygen-glucose deprivation and re-oxygenation injury in HT22 cells: Involvement in reducing oxidative DNA damage. Mol Med Rep. 16:9786–9794. 2017. View Article : Google Scholar : PubMed/NCBI
23	Stetler RA, Gao Y, Zukin RS, Vosler PS, Zhang L, Zhang F, Cao G, Bennett MV and Chen J: Apurinic/apyrimidinic endo-nuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia. Proc Natl Acad Sci USA. 107:3204–3209. 2010. View Article : Google Scholar
24	Liu Y, Eaton ED, Wills TE, McCann SK, Antonic A and Howells DW: Human ischaemic cascade studies using SH-SY5Y cells: A systematic review and meta-analysis. Transl Stroke Res. 9:564–574. 2018. View Article : Google Scholar : PubMed/NCBI
25	Liu Q, Jin Z, Xu Z, Yang H, Li L, Li G, Li F, Gu S, Zong S, Zhou J, et al: Antioxidant effects of ginkgolides and bilobalide against cerebral ischemia injury by activating the Akt/Nrf2 pathway in vitro and in vivo. Cell Stress Chaperones. 24:441–452. 2019. View Article : Google Scholar : PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
27	Li M and Wilson DM III: Human apurinic/apyrimidinic endonuclease 1. Antioxid Redox Signal. 20:678–707. 2014. View Article : Google Scholar
28	Thakur S, Sarkar B, Cholia RP, Gautam N, Dhiman M and Mantha AK: APE1/Ref-1 as an emerging therapeutic target for various human diseases: Phytochemical modulation of its functions. Exp Mol Med. 46:e1062014. View Article : Google Scholar : PubMed/NCBI
29	Shioda N, Han F and Fukunaga K: Role of Akt and ERK signaling in the neurogenesis following brain ischemia. Int Rev Neurobiol. 85:375–387. 2009. View Article : Google Scholar : PubMed/NCBI
30	Nagy Z and Nardai S: Cerebral ischemia/repefusion injury: From bench space to bedside. Brain Res Bull. 134:30–37. 2017. View Article : Google Scholar : PubMed/NCBI
31	Zhou G, Li MH, Tudor G, Lu HT, Kadirvel R and Kallmes D: Remote ischemic conditioning in cerebral diseases and neuro-interventional procedures: Recent researchprogress. Front Neurol. 9:3392018. View Article : Google Scholar
32	Kalani A, Kamat PK, Kalani K and Tyagi N: Epigenetic impact of curcumin on stroke prevention. Metab Brain Dis. 30:427–435. 2015. View Article : Google Scholar
33	Kaur C and Ling EA: Blood brain barrier in hypoxic-ischemic conditions. Curr Neurovasc Res. 5:71–81. 2008. View Article : Google Scholar : PubMed/NCBI
34	Marchiani A, Rozzo C, Fadda A, Delogu G and Ruzza P: Curcumin and curcumin-like molecules: From spice to drugs. Curr Med Chem. 21:204–222. 2014. View Article : Google Scholar
35	Xie CJ, Gu AP, Cai J, Wu Y and Chen RC: Curcumin protects neural cells against ischemic injury in N2a cells and mouse brain with ischemic stroke. Brain Behav. 8:e009212018. View Article : Google Scholar : PubMed/NCBI
36	Zhang Y, Fang M, Sun Y, Zhang T, Shi N, Li J, Jin L, Liu K and Fu J: Curcumin attenuates cerebral ischemia injury in Sprague-Dawley rats and PC12 cells by suppressing overactivated autophagy. J Photochem Photobiol B. 184:1–6. 2018. View Article : Google Scholar : PubMed/NCBI
37	Li P, Stetler RA, Leak RK, Shi Y, Li Y, Yu W, Bennett MVL and Chen J: Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery. Neuropharmacology. 134:208–217. 2018. View Article : Google Scholar
38	Zhao M, Zhu P, Fujino M, Zhuang J, Guo H, Sheikh I, Zhao L and Li XK: Oxidative stress in hypoxic-ischemic encephalopathy: Molecular mechanisms and therapeutic strategies. Int J Mol Sci. 17:E20782016. View Article : Google Scholar : PubMed/NCBI
39	Bavarsad K, Barreto GE, Hadjzadeh MA and Sahebkar A: Protective effects of curcumin against ischemia-reperfusion injury in the nervous system. Mol Neurobiol. 56:1391–1404. 2019. View Article : Google Scholar
40	Chen H, Yoshioka H, Kim GS, Jung JE, Okami N, Sakata H, Maier CM, Narasimhan P, Goeders CE and Chan PH: Oxidative stress in ischemic brain damage: Mechanisms of cell death and potential molecular targets for neuroprotection. Antioxid Redox Signal. 14:1505–1517. 2011. View Article : Google Scholar
41	Li P, Hu X, Gan Y, Gao Y, Liang W and Chen J: Mechanistic insight into DNA damage and repair in ischemic stroke: Exploiting the base excision repair pathway as a model of neuro-protection. Antioxid Redox Signal. 14:1905–1918. 2011. View Article : Google Scholar
42	Li H, Zhong C, Wang Q, Chen W and Yuan Y: Curcumin is an APE1 redox inhibitor and exhibits an antiviral activity against KSHV replication and pathogenesis. Antiviral Res. 167:98–103. 2019. View Article : Google Scholar : PubMed/NCBI
43	Sarkar B, Dhiman M, Mittal S and Mantha AK: Curcumin revitalizes Amyloid beta (25-35)-induced and organophosphate pesticides pestered neurotoxicity in SH-SY5Y and IMR-32 cells via activation of APE1 and Nrf2. Metab Brain Dis. 32:2045–2061. 2017. View Article : Google Scholar : PubMed/NCBI
44	Zaky A, Mahmoud M, Awad D, El Sabaa BM, Kandeel KM and Bassiouny AR: Valproic acid potentiates curcumin-mediated neuroprotection in lipopolysaccharide induced rats. Front Cell Neurosci. 8:3372014. View Article : Google Scholar : PubMed/NCBI
45	Chen SD, Yang DI, Lin TK, Shaw FZ, Liou CW and Chuang YC: Roles of oxidative stress, apoptosis, PGC-1α and mitochondrial biogenesis in cerebral ischemia. Int J Mol Sci. 12:7199–7215. 2011. View Article : Google Scholar
46	Zhao J, Yu S, Zheng W, Feng G, Luo G, Wang L and Zhao Y: Curcumin improves outcomes and attenuates focal cerebral ischemic injury via antiapoptotic mechanisms in rats. Neurochem Res. 35:374–379. 2010. View Article : Google Scholar
47	Wang Q, Sun AY, Simonyi A, Jensen MD, Shelat PB, Rottinghaus GE, MacDonald RS, Miller DK, Lubahn DE, Weisman GA and Sun GY: Neuroprotective mechanisms of curcumin against cerebral ischemia-induced neuronal apoptosis and behavioral deficits. J Neurosci Res. 82:138–148. 2005. View Article : Google Scholar : PubMed/NCBI
48	Lee YR, Kim KM, Jeon BH and Choi S: Extracellularly secreted APE1/Ref-1 triggers apoptosis in triple-negative breast cancer cells via RAGE binding, which is mediated through acetylation. Oncotarget. 6:23383–23398. 2015.PubMed/NCBI
49	Muller UR, Dudler T, Schneider T, Crameri R, Fischer H, Skrbic D, Maibach R, Blaser K and Suter M: Type I skin reactivity to native and recombinant phospholipase A2 from honeybee venom is similar. J Allergy Clin Immunol. 96:395–402. 1995. View Article : Google Scholar : PubMed/NCBI
50	Tell G, Quadrifoglio F, Tiribelli C and Kelley MR: The many functions of APE1/Ref-1: Not only a DNA repair enzyme. Antioxid Redox Signal. 11:601–620. 2009. View Article : Google Scholar
51	Shan JL, He HT, Li MX, Zhu JW, Cheng Y, Hu N, Wang G, Wang D, Yang XQ, He Y, et al: APE1 promotes antioxidant capacity by regulating Nrf-2 function through a redox-dependent mechanism. Free Radic Biol Med. 78:11–22. 2015. View Article : Google Scholar
52	Xie J, Zhang L, Li M, Du J, Zhou L, Yang S, Zeng L, Li Z, Wang G and Wang D: Functional analysis of the involvement of apurinic/apyrimidinic endonuclease 1 in the resistance to melphalan in multiple myeloma. BMC Cancer. 14:112014. View Article : Google Scholar : PubMed/NCBI
53	Fan YY, Hu WW, Nan F and Chen Z: Postconditioning-induced neuroprotection, mechanisms and applications in cerebral ischemia. Neurochem Int. 107:43–56. 2017. View Article : Google Scholar : PubMed/NCBI
54	Matsuda S, Nakagawa Y, Tsuji A, Kitagishi Y, Nakanishi A and Murai T: Implications of PI3K/AKT/PTEN signaling on superoxide dismutases expression and in the pathogenesis of Alzheimer's disease. Diseases. 6:E282018. View Article : Google Scholar : PubMed/NCBI
55	Davis SM and Pennypacker KR: Targeting antioxidant enzyme expression as a therapeutic strategy for ischemic stroke. Neurochem Int. 107:23–32. 2017. View Article : Google Scholar : PubMed/NCBI
56	Sang Q, Sun D, Chen Z and Zhao W: NGF and PI3K/Akt signaling participate in the ventral motor neuronal protection of curcumin in sciatic nerve injury rat models. Biomed Pharmacother. 103:1146–1153. 2018. View Article : Google Scholar : PubMed/NCBI
57	Srivastava P, Dhuriya YK, Kumar V, Srivastava A, Gupta R, Shukla RK, Yadav RS, Dwivedi HN, Pant AB and Khanna VK: PI3K/Akt/GSK3beta induced CREB activation ameliorates arsenic mediated alterations in NMDA receptors and associated signaling in rat hippocampus: Neuroprotective role of curcumin. Neurotoxicology. 67:190–205. 2018. View Article : Google Scholar : PubMed/NCBI
58	Zhong W, Qian K, Xiong J, Ma K, Wang A and Zou Y: Curcumin alleviates lipopolysaccharide induced sepsis and liver failure by suppression of oxidative stress-related inflammation via PI3K/AKT and NF-KB related signaling. Biomed Pharmacother. 83:302–313. 2016. View Article : Google Scholar : PubMed/NCBI