Skip to main content

Advertisement

SpringerLink
Log in

Strategy to Suppress Oxidative Damage-Induced Neurotoxicity in PC12 Cells by Curcumin: the Role of ROS-Mediated DNA Damage and the MAPK and AKT Pathways

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Oxidative damage plays a key role in causation and progression of neurodegenerative diseases. Inhibition of oxidative stress represents one of the most effective ways in treating human neurologic diseases. Herein, we evaluated the protective effect of curcumin on PC12 cells against H2O2-induced neurotoxicity and investigated its underlying mechanism. The results indicated that curcumin pre-treatment significantly suppressed H2O2-induced cytotoxicity, inhibited the loss of mitochondrial membrane potential (Δψm) through regulation of Bcl-2 family expression, and ultimately reversed H2O2-induced apoptotic cell death in PC12 cells. Attenuation of caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage, DNA damage, and accumulation of reactive oxygen species (ROS) all confirmed its protective effects. Moreover, curcumin markedly alleviated the dysregulation of the MAPK and AKT pathways induced by H2O2. Taken together, our findings suggest that the strategy of using curcumin could be a highly effective way in combating oxidative damage-mediated human neurodegenerative diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Lagowska-Lenard M, Bielewicz J, Raszewski G et al (2008) Oxidative stress in cerebral stroke. Pol Merkur Lekarski 25(147):205–208

    CAS  PubMed  Google Scholar 

  2. Zhou C, Huang Y, Przedborski S (2008) Oxidative stress in Parkinson’s disease: a mechanism of pathogenic and therapeutic significance. Ann N Y Acad Sci 1147:93–104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Su B, Wang X, Nunomura A et al (2008) Oxidative stress signaling in Alzheimer’s disease. Curr Alzheimer Res 5(6):525–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Butterfield DA, Lauderback CM (2002) Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med 32(11):1050–1060

    Article  CAS  PubMed  Google Scholar 

  5. Sultana R, Perluigi M, Butterfield DA (2006) Protein oxidation and lipid peroxidation in brain of subjects with Alzheimer’s disease: insights into mechanism of neurodegeneration from redox proteomics. Antioxid Redox Signal 8(11–12):2021–2037

    Article  CAS  PubMed  Google Scholar 

  6. Moreira PI, Nunomura A, Nakamura M et al (2008) Nucleic acid oxidation in Alzheimer disease. Free Radic Biol Med 44(8):1493–1505

    Article  CAS  PubMed  Google Scholar 

  7. Pratico D, Clark CM, Liun F et al (2002) Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease. Arch Neurol 59(6):972–976

    Article  PubMed  Google Scholar 

  8. Butterfield DA, Reed TT, Perluigi M et al (2007) Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer’s disease. Brain Res 1148:243–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Maheshwari A, Misro MM, Aggarwal A et al (2009) Pathways involved in testicular germ cell apoptosis induced by H2O2 in vitro. FEBS J 276(3):870–881

    Article  CAS  PubMed  Google Scholar 

  10. Gupta A, Vij G, Sharma S et al (2009) Curcumin, a polyphenolic antioxidant, attenuates chronic fatigue syndrome in murine water immersion stress model. Immunobiology 214(1):33–39

    Article  CAS  PubMed  Google Scholar 

  11. Dai F, Chen WF, Zhou B et al (2009) Antioxidative effects of curcumin and its analogues against the free-radical-induced peroxidation of linoleic acid in micelles. Phytother Res 23(9):1220–1228

    Article  CAS  PubMed  Google Scholar 

  12. Karmakar S, Banik NL, Ray SK (2007) Curcumin suppressed anti-apoptotic signals and activated cysteine proteases for apoptosis in human malignant glioblastoma U87MG cells. Neurochem Res 32(12):2103–2113

    Article  CAS  PubMed  Google Scholar 

  13. Devasena T, Menon VP, Rajasekharan KN (2006) Prevention of 1,2-dimethylhydrazine-induced circulatory oxidative stress by bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione during colon carcinogenesis. Pharmacol Rep 58(2):229–235

    CAS  PubMed  Google Scholar 

  14. Jaruga E, Bielak-Zmijewska A, Sikora E et al (1998) Glutathione-independent mechanism of apoptosis inhibition by curcumin in rat thymocytes. Biochem Pharmacol 56(8):961–965

    Article  CAS  PubMed  Google Scholar 

  15. Somasundaram S, Edmund NA, Moore DT et al (2002) Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res 62(13):3868–3875

    CAS  PubMed  Google Scholar 

  16. Chan WH, Wu CC, Yu JS (2003) Curcumin inhibits UV irradiation-induced oxidative stress and apoptotic biochemical changes in human epidermoid carcinoma A431 cells. J Cell Biochem 90(2):327–338

    Article  CAS  PubMed  Google Scholar 

  17. Jiang J, Wang W, Sun YJ et al (2007) Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventing blood-brain barrier damage. Eur J Pharmacol 561(1–3):54–62

    Article  CAS  PubMed  Google Scholar 

  18. Siddiqui MA, Kashyap MP, Kumar V et al (2010) Differential protection of pre-, co- and post-treatment of curcumin against hydrogen peroxide in PC12 cells. Hum Exp Toxicol 30(3):192–198

    Article  PubMed  Google Scholar 

  19. Fan C, Chen J, Wang Y et al (2013) Selenocystine potentiates cancer cell apoptosis induced by 5-fluorouracil by triggering reactive oxygen species-mediated DNA damage and inactivation of the ERK pathway. Free Radic Biol Med 65:305–316

    Article  CAS  PubMed  Google Scholar 

  20. Fan C, Zheng W, Fu X et al (2014) Enhancement of auranofin-induced lung cancer cell apoptosis by selenocystine, a natural inhibitor of TrxR1 in vitro and in vivo. Cell Death Dis 5:e1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim R (2005) Recent advances in understanding the cell death pathways activated by anticancer therapy. Cancer 103(8):1551–1560

    Article  CAS  PubMed  Google Scholar 

  22. Festjens N, van Gurp M, van Loo G et al (2004) Bcl-2 family members as sentinels of cellular integrity and role of mitochondrial intermembrane space proteins in apoptotic cell death. Acta Haematol 111(1–2):7–27

    CAS  PubMed  Google Scholar 

  23. van Gurp M, Festjens N, van Loo G et al (2003) Mitochondrial intermembrane proteins in cell death. Biochem Biophys Res Commun 304(3):487–497

    Article  PubMed  Google Scholar 

  24. Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2(9):647–656

    Article  CAS  PubMed  Google Scholar 

  25. Wei MC, Zong WX, Cheng EH et al (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292(5517):727–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81(2):807–869

    CAS  PubMed  Google Scholar 

  27. Dudek H, Datta SR, Franke TF et al (1997) Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275(5300):661–665

    Article  CAS  PubMed  Google Scholar 

  28. Burke RE (2007) Inhibition of mitogen-activated protein kinase and stimulation of Akt kinase signaling pathways: two approaches with therapeutic potential in the treatment of neurodegenerative disease. Pharmacol Ther 114(3):261–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Read DE, Gorman AM (2009) Involvement of Akt in neurite outgrowth. Cell Mol Life Sci 66(18):2975–2984

    Article  CAS  PubMed  Google Scholar 

  30. Xia Z, Sun B, Zheng Y et al (2006) Changes of nitric oxide, oxide free radicals, and systolic arterial blood pressure in rats with experimental lymphatostatic encephalopathy. Clin Hemorheol Microcirc 34(1–2):207–211

    CAS  PubMed  Google Scholar 

  31. Pal A, Kumar A, Prasad R (2014) Predictive association of copper metabolism proteins with Alzheimer’s disease and Parkinson’s disease: a preliminary perspective. Biometals 27(1):25–31

    Article  CAS  PubMed  Google Scholar 

  32. Jaronen M, Vehvilainen P, Malm T et al (2013) Protein disulfide isomerase in ALS mouse glia links protein misfolding with NADPH oxidase-catalyzed superoxide production. Hum Mol Genet 22(4):646–655

    Article  CAS  PubMed  Google Scholar 

  33. Shivasharan BD, Nagakannan P, Thippeswamy BS et al (2013) Protective effect of Calendula officinalis Linn. flowers against 3-nitropropionic acid induced experimental Huntington’s disease in rats. Drug Chem Toxicol 36(4):466–473

    Article  CAS  PubMed  Google Scholar 

  34. Crispo JA, Piche M, Ansell DR et al (2014) Protective effects of methyl gallate on H2O2-induced apoptosis in PC12 cells. Biochem Biophys Res Commun 393(4):773–778

    Article  Google Scholar 

  35. Ahsan H, Parveen N, Khan NU et al (1999) Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. Chem Biol Interact 121(2):161–175

    Article  CAS  PubMed  Google Scholar 

  36. Park SY, Kim HS, Cho EK et al (2008) Curcumin protected PC12 cells against beta-amyloid-induced toxicity through the inhibition of oxidative damage and tau hyperphosphorylation. Food Chem Toxicol 46(8):2881–2887

    Article  CAS  PubMed  Google Scholar 

  37. Chen J, Tang XQ, Zhi JL et al (2006) Curcumin protects PC12 cells against 1-methyl-4-phenylpyridinium ion-induced apoptosis by bcl-2-mitochondria-ROS-iNOS pathway. Apoptosis 11(6):943–953

    Article  CAS  PubMed  Google Scholar 

  38. Bengmark S (2006) Curcumin, an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases. Jpen 30(1):45–51

    Article  CAS  Google Scholar 

  39. Raza H, John A, Brown EM, Benedict S, Kambal A et al (2008) Alterations in mitochondrial respiratory functions, redox metabolism and apoptosis by oxidant 4-hydroxynonenal and antioxidants curcumin and melatonin in PC12 cells. Toxicol Appl Pharmacol 226(2):161–168

    Article  CAS  PubMed  Google Scholar 

  40. Okada H, Mak TW (2004) Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 4(8):592–603

    Article  CAS  PubMed  Google Scholar 

  41. Chen T, Wong YS (2009) Selenocystine induces reactive oxygen species-mediated apoptosis in human cancer cells. Biomed Pharmacother 63(2):105–113

    Article  CAS  PubMed  Google Scholar 

  42. Chen T, Zheng W, Wong YS et al (2008) Mitochondria-mediated apoptosis in human breast carcinoma MCF-7 cells induced by a novel selenadiazole derivative. Biomed Pharmacother 62(2):77–84

    Article  CAS  PubMed  Google Scholar 

  43. Fecker LF, Geilen CC, Tchernev G et al (2006) Loss of proapoptotic Bcl-2-related multidomain proteins in primary melanomas is associated with poor prognosis. J Investig Dermatol 126(6):1366–1371

    Article  CAS  PubMed  Google Scholar 

  44. Krantic S, Mechawar N, Reix S et al (2007) Apoptosis-inducing factor: a matter of neuron life and death. Prog Neurobiol 81(3):179–196

    Article  CAS  PubMed  Google Scholar 

  45. Boldt S, Weidle UH, Kolch W (2002) The role of MAPK pathways in the action of chemotherapeutic drugs. Carcinogenesis 23(11):1831–1838

    Article  CAS  PubMed  Google Scholar 

  46. McCubrey JA, Steelman LS, Abrams SL et al (2006) Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzym Regul 46:249–279

    Article  CAS  Google Scholar 

  47. Ikonomidou C, Kaindl AM (2011) Neuronal death and oxidative stress in the developing brain. Antioxid Redox Signal 14(8):1535–1550

    Article  CAS  PubMed  Google Scholar 

  48. Valko M, Leibfritz D, Moncol J et al (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39(1):44–84

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81471212, 81271275, 81070947, and 30770759 to B.-L. Sun; No. 81271276 to F. Zhang) and by the Natural Science Foundation of Shandong (No. ZR2012HZ006 to B.-L. Sun).

Author information

Authors and Affiliations

  1. School of Basic Medicine, Taishan Medical University, Taian, 271000, Shandong, China

    Xiao-yan Fu & Jing-yi Sun

  2. Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, 271000, Shandong, China

    Xiao-yan Fu, Ming-feng Yang, Da-wei Li, Xiao-yi Yang, Zong-yong Zhang, Lei-lei Mao, Shuai Zhang, Feng-ze Wang, Feng Zhang, Cun-dong Fan & Bao-liang Sun

  3. Department of Neurosurgery, Huxi Hospital, Jining Medical University, Shanxian, 274300, Shandong, China

    Ming-zhi Cao

  4. Department of Neurology and Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Feng Zhang

  5. Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, 271000, Shandong, China

    Bao-liang Sun

Authors
  1. Xiao-yan Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ming-feng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ming-zhi Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Da-wei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao-yi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing-yi Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zong-yong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lei-lei Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shuai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Feng-ze Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Feng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Cun-dong Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Bao-liang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Cun-dong Fan or Bao-liang Sun.

Additional information

Xiao-yan Fu and Ming-feng Yang are co-first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 53 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fu, Xy., Yang, Mf., Cao, Mz. et al. Strategy to Suppress Oxidative Damage-Induced Neurotoxicity in PC12 Cells by Curcumin: the Role of ROS-Mediated DNA Damage and the MAPK and AKT Pathways. Mol Neurobiol 53, 369–378 (2016). https://doi.org/10.1007/s12035-014-9021-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-9021-1

Keywords

Search

Navigation