Skip to main content

Advertisement

SpringerLink
Log in

Protective Effects of Hesperidin Against Amyloid-β (Aβ) Induced Neurotoxicity Through the Voltage Dependent Anion Channel 1 (VDAC1)-Mediated Mitochondrial Apoptotic Pathway in PC12 Cells

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

An Erratum to this article was published on 28 April 2013

Abstract

Amyloid-β (Aβ) is known to exert cytotoxic effects by inducing mitochondrial dysfunction. Additionally, the mitochondrial voltage-dependent anion channel 1 (VDAC1), which is involved in the release of apoptotic proteins with possible relevance in Alzheimer’s disease (AD) neuropathology, plays an important role in maintaining mitochondrial function and integrity. However, the application of therapeutic drugs, especially natural products in (AD) therapy via VDAC1-regulated mitochondrial apoptotic pathway has not aroused extensive attention. In the present study, we investigated neuroprotective effects of hesperidin, a bioactive flavonoid compound, on Aβ25–35-induced neurotoxicity in PC12 cells and also examined the potential cellular signalling mechanism. Our results showed that treatment with hesperidin significantly inhibited Aβ25–35-induced apoptosis by reversing Aβ-induced mitochondrial dysfunction, including the mitochondrial permeability transition pore opening, intracellular free calcium increase and reactive oxygen species production. Further study indicated that hesperidin can increase the level of VDAC1 phosphorylation through enhancing the activity of the glycogen synthasekinase-3β and decrease the level of hexokinaseI in mitochondrial, resulting in mitochondrial release of cytochrome c. Furthermore, hesperidin inhibited mitochondria-dependent downstream caspase-mediated apoptotic pathway, such as that involving caspase-9 and caspase-3. These results demonstrate that hesperidin can protect Aβ-induced neurotoxicity via VDAC1-regulated mitochondrial apoptotic pathway, and they raise the possibility that hesperidin could be developed into a clinically valuable treatment for AD and other neuronal degenerative diseases associated with mitochondrial dysfunction.

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

Similar content being viewed by others

Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid-β

DCF-DA:

Dichlorofluorescin diacetate

GSK-3β:

Glycogen synthasekinase-3β

HXKI:

HexokinaseI

MDA:

Malondialdehyde

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-H-tetrazolium bromide

mPTP:

Mitochondrial permeability transition pore

ROS:

Reactive oxygen species

VDAC1:

Voltage dependent anion channel 1

References

  1. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307:1282–1288

    Article  PubMed  CAS  Google Scholar 

  2. Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639

    Article  PubMed  CAS  Google Scholar 

  3. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    Article  PubMed  CAS  Google Scholar 

  4. Moreira PI, Cardoso SM, Santos MS, Oliveira CR (2006) The key role of mitochondria in Alzheimer’s disease. J Alzheimers Dis 9:101–110

    PubMed  CAS  Google Scholar 

  5. Cha MY, Han SH, Son SM, Hong HS, Choi YJ, Byun J, Mook-Jung I (2012) Mitochondria-specific accumulation of amyloid beta induces mitochondrial dysfunction leading to apoptotic cell death. PLoS ONE 7:e34929

    Article  PubMed  CAS  Google Scholar 

  6. Picone P, Carrotta R, Montana G, Nobile MR, San Biagio PL, Di Carlo M (2009) Abeta oligomers and fibrillar aggregates induce different apoptotic pathways in LAN5 neuroblastoma cell cultures. Biophys J 96:4200–4211

    Article  PubMed  CAS  Google Scholar 

  7. Manczak M, Reddy PH (2012) Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer’s disease. Hum Mol Genet 21:5131–5146

    Article  PubMed  CAS  Google Scholar 

  8. Ren R, Zhang Y, Li B, Wu Y (2011) Effect of beta-amyloid (25–35) on mitochondrial function and expression of mitochondrial permeability transition pore proteins in rat hippocampal neurons. J Cell Biochem 112:1450–1457

    Article  PubMed  CAS  Google Scholar 

  9. Cuadrado-Tejedor M, Vilarino M, Cabodevilla F, Del Rio J, Frechilla D, Perez-Mediavilla A (2011) Enhanced expression of the voltage-dependent anion channel 1 (VDAC1) in Alzheimer’s disease transgenic mice: an insight into the pathogenic effects of amyloid-beta. J Alzheimers Dis 23:195–206

    PubMed  CAS  Google Scholar 

  10. Galati EM, Monforte MT, Kirjavainen S, Forestieri AM, Trovato A, Tripodo MM (1994) Biological effects of hesperidin, a citrus flavonoid. (Note I): antiinflammatory and analgesic activity. Farmaco 40:709–712

    PubMed  CAS  Google Scholar 

  11. Agati G, Azzarello E, Pollastri S, Tattini M (2012) Flavonoids as antioxidants in plants: location and functional significance. Plant Sci 196:67–76

    Article  PubMed  CAS  Google Scholar 

  12. Ramful D, Bahorun T, Bourdon E, Tarnus E, Aruoma OI (2010) Bioactive phenolics and antioxidant propensity of flavedo extracts of Mauritian citrus fruits: potential prophylactic ingredients for functional foods application. Toxicology 278:75–87

    Article  PubMed  CAS  Google Scholar 

  13. Wilmsen PK, Spada DS, Salvador M (2005) Antioxidant activity of the flavonoid hesperidin in chemical and biological systems. J Agric Food Chem 53:4757–4761

    Article  PubMed  CAS  Google Scholar 

  14. Arafa HM, Aly HA, Abd-Ellah MF, El-Refaey HM (2009) Hesperidin attenuates benzo[alpha] pyrene-induced testicular toxicity in rats via regulation of oxidant/antioxidant balance. Toxicol Ind Health 25:417–427

    Article  PubMed  CAS  Google Scholar 

  15. Choi EJ (2008) Antioxidative effects of hesperetin against 7,12-dimethylbenz(a) anthracene-induced oxidative stress in mice. Life Sci 82:1059–1064

    Article  PubMed  CAS  Google Scholar 

  16. Viswanatha GL, Shylaja H, Sandeep Rao KS, Santhosh Kumar VR, Jagadeesh M (2012) Hesperidin ameliorates immobilization-stress-induced behavioral and biochemical alterations and mitochondrial dysfunction in mice by modulating nitrergic pathway. ISRN Pharmacol 2012:479570

    PubMed  CAS  Google Scholar 

  17. Gaur V, Aggarwal A, Kumar A (2011) Possible nitric oxide mechanism in the protective effect of hesperidin against ischemic reperfusion cerebral injury in rats. Indian J Exp Biol 49:609–618

    PubMed  CAS  Google Scholar 

  18. Gaur V, Kumar A (2010) Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Rep 62:635–648

    PubMed  CAS  Google Scholar 

  19. Huang SM, Tsai SY, Lin JA, Wu CH, Yen GC (2012) Cytoprotective effects of hesperetin and hesperidin against amyloid beta-induced impairment of glucose transport through downregulation of neuronal autophagy. Mol Nutr Food Res 56:601–609

    Article  PubMed  CAS  Google Scholar 

  20. Chen K, Zhang Q, Wang J, Liu F, Mi M, Xu H, Chen F, Zeng K (2009) Taurine protects transformed rat retinal ganglion cells from hypoxia-induced apoptosis by preventing mitochondrial dysfunction. Brain Res 1279:131–138

    Article  PubMed  CAS  Google Scholar 

  21. Diaz-Prieto N, Herrera-Peco I, de Diego AM, Ruiz-Nuno A, Gallego-Sandin S, Lopez MG, Garcia AG, Cano-Abad MF (2008) Bcl2 mitigates Ca2+ entry and mitochondrial Ca2+ overload through downregulation of L-type Ca2+ channels in PC12 cells. Cell Calcium 44:339–352

    Article  PubMed  CAS  Google Scholar 

  22. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691

    Article  PubMed  CAS  Google Scholar 

  23. Haass C, Selkoe DJ (1993) Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 75:1039–1042

    Article  PubMed  CAS  Google Scholar 

  24. Lorenzo A, Yankner BA (1996) Amyloid fibril toxicity in Alzheimer’s disease and diabetes. Ann N Y Acad Sci 777:89–95

    Article  PubMed  CAS  Google Scholar 

  25. Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW (1991) In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res 563:311–314

    Article  PubMed  CAS  Google Scholar 

  26. Tohda C, Tamura T, Matsuyama S, Komatsu K (2006) Promotion of axonal maturation and prevention of memory loss in mice by extracts of Astragalus mongholicus. Br J Pharmacol 149:532–541

    Article  PubMed  CAS  Google Scholar 

  27. Du H, Yan SS (2010) Mitochondrial permeability transition pore in Alzheimer’s disease: cyclophilin D and amyloid beta. Biochim Biophys Acta 1802:198–204

    Article  PubMed  CAS  Google Scholar 

  28. Ferreiro E, Oliveira CR, Pereira CM (2008) The release of calcium from the endoplasmic reticulum induced by amyloid-beta and prion peptides activates the mitochondrial apoptotic pathway. Neurobiol Dis 30:331–342

    Article  PubMed  CAS  Google Scholar 

  29. Shoshan-Barmatz V, Keinan N, Zaid H (2008) Uncovering the role of VDAC in the regulation of cell life and death. J Bioenerg Biomembr 40:183–191

    Article  PubMed  CAS  Google Scholar 

  30. Pastorino JG, Hoek JB, Shulga N (2005) Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res 65:10545–10554

    Article  PubMed  CAS  Google Scholar 

  31. Koh JY, Yang LL, Cotman CW (1990) Beta-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res 533:315–320

    Article  PubMed  CAS  Google Scholar 

  32. Harris ME, Hensley K, Butterfield DA, Leedle RA, Carney JM (1995) Direct evidence of oxidative injury produced by the Alzheimer’s beta-amyloid peptide (1–40) in cultured hippocampal neurons. Exp Neurol 131:193–202

    Article  PubMed  CAS  Google Scholar 

  33. Green PS, Gridley KE, Simpkins JW (1996) Estradiol protects against beta-amyloid (25–35)-induced toxicity in SK-N-SH human neuroblastoma cells. Neurosci Lett 218:165–168

    Article  PubMed  CAS  Google Scholar 

  34. Alonso AC, Grundke-Iqbal I, Iqbal K (1996) Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med 2:783–787

    Article  PubMed  CAS  Google Scholar 

  35. Hauptmann S, Scherping I, Drose S, Brandt U, Schulz KL, Jendrach M, Leuner K, Eckert A, Muller WE (2009) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging 30:1574–1586

    Article  PubMed  CAS  Google Scholar 

  36. Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med 14:45–53

    Article  PubMed  CAS  Google Scholar 

  37. Devi L, Prabhu BM, Galati DF, Avadhani NG, Anandatheerthavarada HK (2006) Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci 26:9057–9068

    Article  PubMed  CAS  Google Scholar 

  38. Sullivan PG, Brown MR (2005) Mitochondrial aging and dysfunction in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 29:407–410

    Article  PubMed  CAS  Google Scholar 

  39. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15:1437–1449

    Article  PubMed  CAS  Google Scholar 

  40. Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG, Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SS, Wu H (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 304:448–452

    Article  PubMed  CAS  Google Scholar 

  41. Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 31:454–463

    Article  PubMed  CAS  Google Scholar 

  42. Small DH, Gasperini R, Vincent AJ, Hung AC, Foa L (2009) The role of Abeta-induced calcium dysregulation in the pathogenesis of Alzheimer’s disease. J Alzheimers Dis 16:225–233

    PubMed  CAS  Google Scholar 

  43. Hashimoto M, Rockenstein E, Crews L, Masliah E (2003) Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases. Neuromolecular Med 4:21–36

    Article  PubMed  CAS  Google Scholar 

  44. Ahmad ST, Arjumand W, Nafees S, Seth A, Ali N, Rashid S, Sultana S (2012) Hesperidin alleviates acetaminophen induced toxicity in Wistar rats by abrogation of oxidative stress, apoptosis and inflammation. Toxicol Lett 208:149–161

    Article  PubMed  CAS  Google Scholar 

  45. Trivedi PP, Tripathi DN, Jena GB (2011) Hesperetin protects testicular toxicity of doxorubicin in rat: role of NFkappaB, p38 and caspase-3. Food Chem Toxicol 49:838–847

    Article  PubMed  CAS  Google Scholar 

  46. Hwang SL, Yen GC (2008) Neuroprotective effects of the citrus flavanones against H2O2-induced cytotoxicity in PC12 cells. J Agric Food Chem 56:859–864

    Article  PubMed  CAS  Google Scholar 

  47. Yoo BC, Fountoulakis M, Cairns N, Lubec G (2001) Changes of voltage-dependent anion-selective channel proteins VDAC1 and VDAC2 brain levels in patients with Alzheimer’s disease and down syndrome. Electrophoresis 22:172–179

    Article  PubMed  CAS  Google Scholar 

  48. Zaid H, Abu-Hamad S, Israelson A, Nathan I, Shoshan-Barmatz V (2005) The voltage-dependent anion channel-1 modulates apoptotic cell death. Cell Death Differ 12:751–760

    Article  PubMed  CAS  Google Scholar 

  49. Ghosh T, Pandey N, Maitra A, Brahmachari SK, Pillai B (2007) A role for voltage-dependent anion channel Vdac1 in polyglutamine-mediated neuronal cell death. PLoS ONE 2:e1170

    Article  PubMed  Google Scholar 

  50. Abu-Hamad S, Zaid H, Israelson A, Nahon E, Shoshan-Barmatz V (2008) Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: mapping the site of binding. J Biol Chem 283:13482–13490

    Article  PubMed  CAS  Google Scholar 

  51. Shoshan-Barmatz V, Keinan N, Abu-Hamad S, Tyomkin D, Aram L (2010) Apoptosis is regulated by the VDAC1 N-terminal region and by VDAC oligomerization: release of cytochrome c, AIF and Smac/Diablo. Biochim Biophys Acta 1797:1281–1291

    Article  PubMed  CAS  Google Scholar 

  52. Pastorino JG, Hoek JB (2003) Hexokinase II: the integration of energy metabolism and control of apoptosis. Curr Med Chem 10:1535–1551

    Article  PubMed  CAS  Google Scholar 

  53. Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V (2004) In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death. Biochem J 377:347–355

    Article  PubMed  CAS  Google Scholar 

  54. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Robey RB, Hay N (2004) Hexokinase–mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 16:819–830

    Article  PubMed  CAS  Google Scholar 

  55. Jo J, Whitcomb DJ, Olsen KM, Kerrigan TL, Lo SC, Bru-Mercier G, Dickinson B, Scullion S, Sheng M, Collingridge G, Cho K (2011) Abeta(1–42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3beta. Nat Neurosci 14:545–547

    Article  PubMed  CAS  Google Scholar 

  56. Jimenez S, Torres M, Vizuete M, Sanchez-Varo R, Sanchez-Mejias E, Trujillo-Estrada L, Carmona-Cuenca I, Caballero C, Ruano D, Gutierrez A, Vitorica J (2011) Age-dependent accumulation of soluble amyloid beta (Abeta) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-alpha (sAPP(alpha)) by modulating phosphatidylinositol 3-kinase (PI3 K)/Akt-GSK-3beta pathway in Alzheimer mouse model. J Biol Chem 286:18414–18425

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The present work was supported by the Scientific Research Fund of Henan University of Science and Technology (No. 09001664).

Author information

Authors and Affiliations

  1. Department of Pathogen Biology, Medical College, Henan University of Science and Technology, Building 6, Anhui, Jianxi District, Luoyang, 471003, People’s Republic of China

    Dong-Mei Wang, Xiao-Ying Zhu, Yong Wang, Wen-Lan Wu & Xiao-Juan Zhang

  2. Department of Biochemistry and Molecular Biology, Medical College, Henan University of Science and Technology, Luoyang, China

    San-Qiang Li

Authors
  1. Dong-Mei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. San-Qiang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-Ying Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen-Lan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiao-Juan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dong-Mei Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, DM., Li, SQ., Zhu, XY. et al. Protective Effects of Hesperidin Against Amyloid-β (Aβ) Induced Neurotoxicity Through the Voltage Dependent Anion Channel 1 (VDAC1)-Mediated Mitochondrial Apoptotic Pathway in PC12 Cells. Neurochem Res 38, 1034–1044 (2013). https://doi.org/10.1007/s11064-013-1013-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-013-1013-4

Keywords

Search

Navigation