Skip to main content
Springer Nature Link
Log in

Resveratrol Protects PC12 Cells from High Glucose-Induced Neurotoxicity Via PI3K/Akt/FoxO3a Pathway

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Diabetes is known to be associated with neurodegenerative diseases. Resveratrol, a plant-derived polyphenolic compound found in red wine, possesses antioxidant properties. In this study, we aimed to investigate the effects of resveratrol on the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt)/FoxO3a pathway in mediating high glucose (HG)-induced injuries in neuronal PC12 cells. PC12 cells were exposed to HG to establish a model of HG neurotoxicity. Results showed that pre-treating PC12 cells with resveratrol before exposure to HG led to increased cell viability, decreased apoptotic cells, and reactive oxygen species generation. Western blot analysis showed that HG decreased the phosphorylation of Akt and FoxO3a and led to the nuclear localization of FoxO3a. These effects were significantly alleviated by resveratrol co-treatment. Furthermore, the protective effects of resveratrol were abolished by PI3K/Akt inhibitor LY294002. All these results demonstrate that resveratrol protected the PC12 cells from HG-induced oxidative stress and apoptosis via the activation of PI3K/Akt/FoxO3a signaling pathway.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Akhter R, Sanphui P, Biswas SC (2014) The essential role of p53-up-regulated modulator of apoptosis (Puma) and its regulation by FoxO3a transcription factor in beta-amyloid-induced neuron death. J Biol Chem 289(15):10812–10822

    Article  CAS  PubMed  Google Scholar 

  • Albani D, Polito L, Signorini A, Forloni G (2010) Neuroprotective properties of resveratrol in different neurodegenerative disorders. BioFactors 36(5):370–376

    Article  CAS  PubMed  Google Scholar 

  • Arab L, Sadeghi R, Walker DG, Lue LF, Sabbagh MN (2011) Consequences of aberrant insulin regulation in the brain: can treating diabetes be effective for Alzheimer’s disease. Curr Neuropharmacol 9(4):693–705

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bournival J, Quessy P, Martinoli MG (2009) Protective effects of resveratrol and quercetin against MPP+-induced oxidative stress act by modulating markers of apoptotic death in dopaminergic neurons. Cell Mol Neurobiol 29(8):1169–1180

    Article  CAS  PubMed  Google Scholar 

  • Bournival J, Francoeur MA, Renaud J, Martinoli MG (2012) Quercetin and sesamin protect neuronal PC12 cells from high-glucose-induced oxidation, nitrosative stress, and apoptosis. Rejuvenation Res 15(3):322–333

    Article  CAS  PubMed  Google Scholar 

  • Cao M, Jiang J, Du Y, Yan P (2012) Mitochondria-targeted antioxidant attenuates high glucose-induced P38 MAPK pathway activation in human neuroblastoma cells. Mol Med Rep 5(4):929–934

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cui H, Kong Y, Zhang H (2012) Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct 2012:646354

    Article  PubMed Central  PubMed  Google Scholar 

  • de la Monte SM, Tong M (2014) Brain metabolic dysfunction at the core of Alzheimer’s disease. Biochem Pharmacol 88(4):548–559

    Article  PubMed  Google Scholar 

  • Foti Cuzzola V, Ciurleo R, Giacoppo S, Marino S, Bramanti P (2011) Role of resveratrol and its analogues in the treatment of neurodegenerative diseases: focus on recent discoveries. CNS Neurol Disord: Drug Targets 10(7):849–862

    Article  CAS  Google Scholar 

  • Hoeijmakers JG, Faber CG, Merkies IS, Waxman SG (2014) Channelopathies, painful neuropathy, and diabetes: which way does the causal arrow point? Trends Mol Med 20(10):544–550

    Article  CAS  PubMed  Google Scholar 

  • Hsieh HL, Yang CM (2013) Role of redox signaling in neuroinflammation and neurodegenerative diseases. Biomed Res Int 2013:484613

    PubMed Central  PubMed  Google Scholar 

  • Jia Y, Mo SJ, Feng QQ, Zhan ML, Ouyang LS, Chen JC, Ma YX, Wu JJ, Lei WL (2014) EPO-dependent activation of PI3K/Akt/FoxO3a signalling mediates neuroprotection in in vitro and in vivo models of Parkinson’s disease. J Mol Neurosci 53(1):117–124

    Article  CAS  PubMed  Google Scholar 

  • Kamal MA, Priyamvada S, Anbazhagan AN, Jabir NR, Tabrez S, Greig NH (2014) Linking Alzheimer’s disease and type 2 diabetes mellitus via aberrant insulin signaling and inflammation. CNS Neurol Disord: Drug Targets 13(2):338–346

    Article  CAS  Google Scholar 

  • Li D, Qu Y, Mao M, Zhang X, Li J, Ferriero D, Mu D (2009) Involvement of the PTEN-AKT-FOXO3a pathway in neuronal apoptosis in developing rat brain after hypoxia-ischemia. J Cereb Blood Flow Metab 29(12):1903–1913

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liu X, Xiao Q, Zhao K, Gao Y (2013) Ghrelin inhibits high glucose-induced PC12 cell apoptosis by regulating TLR4/NF-kappaB pathway. Inflammation 36(6):1286–1294

    Article  CAS  PubMed  Google Scholar 

  • Luque-Contreras D, Carvajal K, Toral-Rios D, Franco-Bocanegra D, Campos-Pena V (2014) Oxidative stress and metabolic syndrome: cause or consequence of Alzheimer’s disease? Oxid Med Cell Longev 2014:497802

    Article  PubMed Central  PubMed  Google Scholar 

  • Martin TF, Grishanin RN (2003) PC12 cells as a model for studies of regulated secretion in neuronal and endocrine cells. Methods Cell Biol 71:267–286

    Article  CAS  PubMed  Google Scholar 

  • Monsalve M, Olmos Y (2011) The complex biology of FOXO. Curr Drug Targets 12(9):1322–1350

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Sakamoto K (2008) Forkhead transcription factor FOXO subfamily is essential for reactive oxygen species-induced apoptosis. Mol Cell Endocrinol 281(1–2):47–55

    Article  CAS  PubMed  Google Scholar 

  • Peng C, Ma J, Gao X, Tian P, Li W, Zhang L (2013) High glucose induced oxidative stress and apoptosis in cardiac microvascular endothelial cells are regulated by FoxO3a. PLoS ONE 8(11):e79739

    Article  PubMed Central  PubMed  Google Scholar 

  • Radi E, Formichi P, Battisti C, Federico A (2014) Apoptosis and oxidative stress in neurodegenerative diseases. J Alzheimers Dis 42(Suppl 3):S125–S152

    PubMed  Google Scholar 

  • Renaud J, Bournival J, Zottig X, Martinoli MG (2014) Resveratrol protects DAergic PC12 cells from high glucose-induced oxidative stress and apoptosis: effect on p53 and GRP75 localization. Neurotox Res 25(1):110–123

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sanphui P, Biswas SC (2013) FoxO3a is activated and executes neuron death via Bim in response to beta-amyloid. Cell Death Dis 4:e625

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Simao F, Matte A, Pagnussat AS, Netto CA, Salbego CG (2012) Resveratrol prevents CA1 neurons against ischemic injury by parallel modulation of both GSK-3beta and CREB through PI3-K/Akt pathways. Eur J Neurosci 36(7):2899–2905

    Article  PubMed  Google Scholar 

  • Styskal J, Van Remmen H, Richardson A, Salmon AB (2012) Oxidative stress and diabetes: what can we learn about insulin resistance from antioxidant mutant mouse models? Free Radic Biol Med 52(1):46–58

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tomlinson DR, Gardiner NJ (2008) Glucose neurotoxicity. Nat Rev Neurosci 9(1):36–45

    Article  CAS  PubMed  Google Scholar 

  • Uranga RM, Katz S, Salvador GA (2013) Enhanced phosphatidylinositol 3-kinase (PI3K)/Akt signaling has pleiotropic targets in hippocampal neurons exposed to iron-induced oxidative stress. J Biol Chem 288(27):19773–19784

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang H, Zhou X, Huang J, Mu N, Guo Z, Wen Q, Wang R, Chen S, Feng ZP, Zheng W (2013) The role of Akt/FoxO3a in the protective effect of venlafaxine against corticosterone-induced cell death in PC12 cells. Psychopharmacology 228(1):129–141

    Article  CAS  PubMed  Google Scholar 

  • Wilk A, Urbanska K, Yang S, Wang JY, Amini S, Del Valle L, Peruzzi F, Meggs L, Reiss K (2011) Insulin-like growth factor-I-forkhead box O transcription factor 3a counteracts high glucose/tumor necrosis factor-alpha-mediated neuronal damage: implications for human immunodeficiency virus encephalitis. J Neurosci Res 89(2):183–198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wu PF, Xie N, Zhang JJ, Guan XL, Zhou J, Long LH, Li YL, Xiong QJ, Zeng JH, Wang F, Chen JG (2013) Resveratrol preconditioning increases methionine sulfoxide reductases A expression and enhances resistance of human neuroblastoma cells to neurotoxins. J Nutr Biochem 24(6):1070–1077

    Article  CAS  PubMed  Google Scholar 

  • Yan LJ (2014) Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress. J Diabetes Res 2014:137919

    PubMed Central  PubMed  Google Scholar 

  • Zhang S, Zhao Y, Xu M, Yu L, Chen J, Yuan Y, Zheng Q, Niu X (2013) FoxO3a modulates hypoxia stress induced oxidative stress and apoptosis in cardiac microvascular endothelial cells. PLoS ONE 8(11):e80342

    Article  PubMed Central  PubMed  Google Scholar 

  • Zheng WH, Kar S, Quirion R (2000) Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells. J Biol Chem 275(50):39152–39158

    Article  CAS  PubMed  Google Scholar 

  • Zhou XM, Zhou ML, Zhang XS, Zhuang Z, Li T, Shi JX, Zhang X (2014) Resveratrol prevents neuronal apoptosis in an early brain injury model. J Surg Res 189(1):159–165

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Medical scientific research funds of Guangdong Province (A2014810) and Graduate student research innovation project of Hunan Province (CX2013B397).

Conflict of interest

The authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory, Affiliated Nanhua Hospital, University of South China, No. 336 Dongfeng South Road, Hengyang, 421001, Hunan Province, People’s Republic of China

    Mi-Hua Liu, Jun He, Tian-Ping Tan, Shao-Jian Wu, Hong-Yun Fu, Jun Liu, Shan Yu, Yu-Dan Chen, Qun-Fang Le & Wei Tian

  2. Department of Pathology, The Third People’s Hospital of Huizhou, Huizhou City, 516002, Guangdong Province, People’s Republic of China

    Xiao-Long Lin

  3. Department of Cardiology, The First Hospital of Changsha, Changsha City, 410005, Hunan Province, People’s Republic of China

    Cong Yuan

  4. Department of Cardiology/Cardiac Catheterisation Lab, Second Xiangya Hospital, Central South University, Changsha City, 410011, Hunan Province, People’s Republic of China

    Heng-Jing Hu

  5. Department of Pathology, Mawangdui Hospital, Changsha City, 410016, Hunan Province, People’s Republic of China

    Yuan Zhang

Authors
  1. Mi-Hua Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Cong Yuan
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Jun He
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Tian-Ping Tan
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Shao-Jian Wu
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Hong-Yun Fu
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Jun Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Shan Yu
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Yu-Dan Chen
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Qun-Fang Le
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Wei Tian
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Heng-Jing Hu
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Yuan Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Xiao-Long Lin
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence to Mi-Hua Liu or Xiao-Long Lin.

Additional information

Cong Yuan contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIFF 275 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, MH., Yuan, C., He, J. et al. Resveratrol Protects PC12 Cells from High Glucose-Induced Neurotoxicity Via PI3K/Akt/FoxO3a Pathway. Cell Mol Neurobiol 35, 513–522 (2015). https://doi.org/10.1007/s10571-014-0147-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-014-0147-5

Keywords