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Protective Effects of (E)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeine Against Hydrogen Peroxide-Induced Injury in PC12 Cells

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Abstract

(E)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeine (HOEC), a naturally caffeic ester isolated from Incarvillea mairei, has been reported to possess anti-inflammatory activity by targeting 5-lipoxygenase. However, its other potential activities have yet to be explored. In this study, we measured antioxidant activity of HOEC using the DPPH free radical-scavenging assay. Then, we exposed rat pheochromocytoma (PC12) cells to hydrogen peroxide (H2O2)-induced damage and investigated the antioxidant activity of HOEC. Cell viability, lactate dehydrogenase (LDH) release, cellular morphology, Hoechst 33342 fluorescent staining, and apoptosis of the PC12 cells were assessed after treatment with 0.3–10 μM HOEC for 2 h and exposure to 600 μM H2O2. Additionally, glutathione reductase (GR), superoxide dismutase (SOD), lipid peroxidation malondialdehyde (MDA), and intracellular reactive oxygen species (ROS) accumulation were assayed after the PC12 cells were exposed to H2O2. To investigate mechanism, apoptosis-related protein were evaluated, including cleaved caspase 3/7, cleaved PARP, Bcl-2, Bcl-XL, and cytochrome c. The results showed that HOEC possessed potent antioxidant activity and pre-treatment with HOEC prior to H2O2 exposure significantly increased cell viability, reduced the release of LDH, ameliorated changes in cell morphology, and inhibited apoptosis. Further, HOEC did the following: reduced intracellular accumulation of ROS and MDA; rescued loss of SOD and GR activities; inhibited activated caspase-3 and caspase-7, cleaved PARP, and cytochrome c release; up-regulated the antiapoptosis-related protein Bcl-2 and Bcl-XL; and down-regulated the apoptosis-related proteins Bax and Bad. These findings suggested that HOEC may be a therapeutic agent for treating oxidative stress-derived neurodegenerative disorders.

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References

  1. Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3:205–214

    Article  CAS  PubMed  Google Scholar 

  2. Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247

    Article  CAS  PubMed  Google Scholar 

  3. Hauser DN, Hastings TG (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol Dis 51:35–42

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Chen SD, Yang DI, Lin TK, Shaw FZ, Liou CW, Chuang YC (2011) Roles of oxidative stress, apoptosis, PGC-1α and mitochondrial biogenesis in cerebral ischemia. Int J Mol Sci 12:7199–7215

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Barber SC, Shaw PJ (2010) Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radic Biol Med 48:629–641

    Article  CAS  PubMed  Google Scholar 

  6. Brieger K, Schiavone S, Miller FJ Jr, Krause K-H (2012) Reactive oxygen species: from health to disease. Swiss Med Wkly 142:w13659

    CAS  PubMed  Google Scholar 

  7. Yu Y, Du J, Wang C, Qian Z (2008) Protection against hydrogen peroxide-induced injury by Z-ligustilide in PC12 cells. Exp Brain Res 184:307–312

    Article  CAS  PubMed  Google Scholar 

  8. Rhee SG (2006) H2O2, a necessary evil for cell signaling. Science 577:1882–1883

    Article  Google Scholar 

  9. Giorgio M, Trinei M, Migliaccio E, Pelicci PG (2007) Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat Rev Mol Cell Bio 8:722–728

    Article  CAS  Google Scholar 

  10. Cho ES, Lee KW, Lee HJ (2008) Cocoa procyanidins protect PC12 cells from hydrogen-peroxide-induced apoptosis by inhibiting activation of p38 MAPK and JNK. Mutat Res-Fundam Mol Mech Mutag 640:123–130

    Article  CAS  Google Scholar 

  11. Li L, Zeng HW, Liu F, Zhang JG, Yue RC, Lu W, Yuan X, Dai WX, Yuan H, Sun QY (2012) Target identification and validation of (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate, an anti-inflammatory natural product. Eur J Inflam 10:297–309

    Google Scholar 

  12. Gülçin İ (2006) Antioxidant activity of caffeic acid (3,4-dihydroxycinnamic acid). Toxicology 217:213–220

    Article  PubMed  Google Scholar 

  13. Göçer H, Gülçin İ (2011) Caffeic acid phenethyl ester (CAPE): correlation of structure and antioxidant properties. Int J Food Sci Nutr 62:821–825

    Article  PubMed  Google Scholar 

  14. Sul D, Kim HS, Lee D, Joo SS, Hwang KW, Park SY (2009) Protective effect of caffeic acid against beta-amyloid-induced neurotoxicity by the inhibition of calcium influx and tau phosphorylation. Life Sci 84:257–262

    Article  CAS  PubMed  Google Scholar 

  15. **ao H, Lv F, Xu W, Zhang L, **g P, Cao X (2011) Deprenyl prevents MPP+-induced oxidative damage in PC12 cells by the upregulation of Nrf2-mediated NQO1 expression through the activation of PI3K/Akt and Erk. Toxicology 290:286–294

    Article  PubMed  Google Scholar 

  16. Muthaiyah B, Essa MM, Chauhan V, Chauhan A (2011) Protective effects of walnut extract against amyloid beta peptide-induced cell death and oxidative stress in PC12 cells. Neurochem Res 36:2096–2103

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Zhang S, Ye J, Dong G (2010) Neuroprotective effect of baicalein on hydrogen peroxide-mediated oxidative stress and mitochondrial dysfunction in PC12 cells. J Mol Neurosci 40:311–320

    Article  PubMed  Google Scholar 

  18. Su YQ, Zhang WD, Zhang C, Liu RH, Shen YH (2008) A new caffeic ester from Incarvillea mairei var. granditlora (Wehrhahn) Grierson. Chin Chem Lett 19:829–831

    Article  CAS  Google Scholar 

  19. Yuan H, Han W, Yang W, Shan L, Zhang W, Sun Q (2011) Total synthesis of natural product (E)-2-(1-hydroxyl-4-oxocyclohexyl)ethyl caffeate as a modulator of leukotriene A4 hydrolase. Acta Chim Sinica 69:2691–2695

  20. Blois MS (1958) Antioxidant determinations by the use of a stable free radical. Nature 181:1199–1200

    Article  CAS  Google Scholar 

  21. Danpure C (1984) Lactate dehydrogenase and cell injury. Cell Biochem Funct 2:144–148

    Article  CAS  PubMed  Google Scholar 

  22. Kryston TB, Georgiev AB, Pissis P, Georgakilas AG (2011) Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res Fundam Mol Mech Mutag 711:193–201

    Article  CAS  Google Scholar 

  23. Kannan K, Jain SK (2000) Oxidative stress and apoptosis. Pathophysiology 7:153–163

    Article  CAS  PubMed  Google Scholar 

  24. Farooqui AA (2014) Effect of exercise on oxidative stress in neurological disorders. Inflamm Oxid Stress Neurol Disord 287–327. doi:10.1007/978-3-319-04111-7_10

  25. Cao W, Dai M, Wang X, Yuan F, Chen F, Zhang W (2013) Protective effect of sesaminol from Sesamum indicum Linn. against oxidative damage in PC12 cells. Cell Biochem Funct 31:560–565

    CAS  PubMed  Google Scholar 

  26. Lee A, Mercader AG, Duchowicz PR, Castro EA, Pomilio AB (2012) QSAR study of the DPPH radical scavenging activity of di (hetero) arylamines derivatives of benzo [b] thiophenes, halophenols and caffeic acid analogues. Chemom Intell Lab Syst 116:33–40

    Article  CAS  Google Scholar 

  27. Huang Y, ** M, Pi R, Zhang J, Chen M, Ouyang Y, Liu A, Chao X, Liu P, Liu J (2013) Protective effects of caffeic acid and caffeic acid phenethyl ester against acrolein-induced neurotoxicity in HT22 mouse hippocampal cells. Neurosci Lett 535:146–151

    Article  CAS  PubMed  Google Scholar 

  28. Barros Silva R, Santos N, Martins N, Ferreira D, Barbosa F Jr, Oliveira Souza V, Kinoshita A, Baffa O, Del-Bel E, Santos A (2013) Caffeic acid phenethyl ester protects against the dopaminergic neuronal loss induced by 6-hydroxydopamine in rats. Neuroscience 233:86–94

    Article  CAS  PubMed  Google Scholar 

  29. Guo X, Shen L, Tong Y, Zhang J, Wu G, He Q, Yu S, Ye X, Zou L, Zhang Z (2013) Antitumor activity of caffeic acid 3,4-dihydroxyphenethyl ester and its pharmacokinetic and metabolic properties. Phytomedicine 20:904–912

    Article  CAS  PubMed  Google Scholar 

  30. Nathan C, Cunningham-Bussel A (2013) Beyond oxidative stress: an immunologist’s guide to reactive oxygen species. Nat Rev Immunol 13:349–361

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Wållberg M, Bergquist J, Achour A, Breij E, Harris RA (2007) Malondialdehyde modification of myelin oligodendrocyte glycoprotein leads to increased immunogenicity and encephalitogenicity. Eur J Immunol 37:1986–1995

    Article  PubMed  Google Scholar 

  32. Zhu K-X, Guo X, Guo X-N, Peng W, Zhou H-M (2013) Protective effects of wheat germ protein isolate hydrolysates (WGPIH) against hydrogen peroxide-induced oxidative stress in PC12 cells. Food Res Int 53:297–303

    Article  CAS  Google Scholar 

  33. Ochiai T, Soeda S, Ohno S, Tanaka H, Shoyama Y, Shimeno H (2004) Crocin prevents the death of PC-12 cells through sphingomyelinase-ceramide signaling by increasing glutathione synthesis. Neurochem Int 44:321–330

    Article  CAS  PubMed  Google Scholar 

  34. Hyman BT, Yuan J (2012) Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology. Nat Rev Neurosci 13:395–406

    Article  CAS  PubMed  Google Scholar 

  35. Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG (2010) PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10:293–301

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Ferguson-Miller S, Hiser C, Liu J (2012) Gating and regulation of the cytochrome c oxidase proton pump. BBA Bioenergetics 1817:489–494

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Uttara B, Singh AV, Zamboni P, Mahajan R (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7:65

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Persson T, Popescu BO, Cedazo-Minguez A (2014) Oxidative stress in Alzheimer’s disease: why did antioxidant therapy fail? Oxidative Med Cell Longev. doi:10.1155/2014/427318

  39. Agostinho P, Cunha RA, Oliveira C (2010) Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Des 16:2766–2778

    Article  CAS  PubMed  Google Scholar 

  40. Mrak RE, Griffin WST (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26:349–354

    Article  CAS  PubMed  Google Scholar 

  41. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Peterson LJ, Flood PM (2012) Oxidative stress and microglial cells in Parkinson’s disease. Mediators Inflamm. doi:10.1155/2012/401264

  43. Sutliff R, Porter K (2011) Hypoxia induces pulmonary artery endothelial 5-lipoxygenase via increased oxidative stress. Am J Respir Crit Care Med 183:A5493

    Google Scholar 

  44. Li C, Zhang W, Fang S, Lu Y, Zhang L, Qi L, Huang X, Huang X, Wei E (2010) Baicalin attenuates oxygen–glucose deprivation-induced injury by inhibiting oxidative stress-mediated 5-lipoxygenase activation in PC12 cells. Acta Pharmacol Sin 31:137–144

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Czapski GA, Czubowicz K, Strosznajder RP (2012) Evaluation of the antioxidative properties of lipoxygenase inhibitors. Pharmacol Rep 64:1179–1188

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The work was supported by the following programs: NCET Foundation, NSFC (81230090, 1302658), Shanghai Leading Academic Discipline Project (B906), Shanghai Engineering Research Center for the Preparation of Bioactive Natural Products (10DZ2251300), the Scientific Foundation of Shanghai China (12401900801, 13401900101) and the National Key Technology R&D Program of China (2012BAI29B06).

Conflict of interest

There are no competing interests.

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Authors and Affiliations

  1. School of Pharmacy, Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Bingyang Chen, Rongcai Yue, Huawu Zeng, Wanlin Chang, Na Gao, **ng Yuan, Weidong Zhang & Lei Shan

  2. School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, People’s Republic of China

    Rongcai Yue & Weidong Zhang

  3. Department of Clinical Pharmacology, Bei**g Military Command General Hospital, Bei**g, 100700, People’s Republic of China

    Yongge Yang

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  1. Bingyang Chen
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Correspondence to Weidong Zhang or Lei Shan.

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Bingyang Chen, Rongcai Yue and Yongge Yang contributed equally to this work.

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Chen, B., Yue, R., Yang, Y. et al. Protective Effects of (E)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeine Against Hydrogen Peroxide-Induced Injury in PC12 Cells. Neurochem Res 40, 531–541 (2015). https://doi.org/10.1007/s11064-014-1498-5

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