SpringerLink
Log in

Diazoxide Pretreatment Prevents Aβ1–42 Induced Oxidative Stress in Cholinergic Neurons Via Alleviating NOX2 Expression

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

Abstract

The aggregation and accumulation of amyloid-β (Aβ) plays a significant role in the pathogenesis of Alzheimer’s disease. Aβ is known to increase free radical production in neuronal cells, leading to oxidative stress and cell death. Diazoxide (DZ), a highly selective drug capable of opening mitochondrial ATP-sensitive potassium channels, has neuroprotective effects against neuronal cell death. However, the mechanism through which DZ protects cholinergic neurons against Aβ-induced oxidative injury is still unclear. The present study was designed to investigate the effects of DZ pretreatment against Aβ1–42 induced oxidative damage and cytotoxicity. Through measures of DZ effects on Aβ1–42 induced cellular damage, reactive oxygen species (ROS) and MDA generation and expressions of gp91phox and p47phox in cholinergic neurons, new insights into the neuroprotective mechanisms can be derived. Aβ1–42 significantly decreased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide levels and increased ROS and MDA production; all effects were attenuated by pretreatment with DZ or diphenyleneiodonium chloride (a NOX2 inhibitor). Pretreatment with DZ also attenuated the upregulation of NOX2 subunits (gp91phox and p47phox) induced by Aβ1–42. Since NOX2 is one of the main sources of free radicals, these results suggest that DZ can counteract Aβ1–42 induced oxidative stress and associated cell death by reducing the level of ROS and MDA, in part, by alleviating NOX2 expression.

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
EUR 32.99 /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

Similar content being viewed by others

References

  1. Sultana R, Butterfield DA (2010) Role of oxidative stress in the progression of Alzheimer’s disease. J Alzheimers Dis 19:341–353

    PubMed  Google Scholar 

  2. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Sheng B, Wang X, Su B et al (2012) Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease. J Neurochem 120:419–429

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Wang X, Su B, Lee HG et al (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 29:9090–9103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Zhu **aolei, Chen Cong, Ye Dan et al (2012) Diammonium glycyrrhizinate upregulates PGC-1a and protects against Ab1–42-induced neurotoxicity. PLoS ONE 7:e35823

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Petrozzi L, Ricci G, Giglioli N et al (2007) Mitochondria and neurodegeneration. Biosci Rep 27:87–104

    Article  CAS  PubMed  Google Scholar 

  7. Correia Sónia C, Carvalho Cristina et al (2010) Mitochondrial preconditioning: a potential neuroprotective Strategy. Front Aging Neurosci 2:138

    PubMed Central  PubMed  Google Scholar 

  8. Chen Shan, Meng **an-Fang, Zhang Chun (2013) Role of NADPH oxidase-mediated reactive oxygen species in podocyte injury. Biomed Res Int 2013:839761

    PubMed Central  PubMed  Google Scholar 

  9. Gao Hui-Ming, Zhou Hui, Hong Jau-Shyong (2012) NADPH oxidases: novel therapeutic targets for neurodegenerative diseases. Trends Pharmacol Sci 33:295–303

    Article  PubMed Central  PubMed  Google Scholar 

  10. Ansari MA, Scheff SW (2011) NADPH-oxidase activation and cognition in Alzheimer disease progression. Free Radical Biol Med 51:171–178

    Article  CAS  Google Scholar 

  11. Shimohama S (2011) Activation of NADPH oxidase in Alzheimer’s disease brains. Biochem Biophys Res Commun 273:5–9

    Article  Google Scholar 

  12. Virgili Noe, Mancera Pilar, Wappenhans Blanca et al (2013) KATP channel opener diazoxide prevents neurodegeneration: a new mechanism of action via antioxidative pathway activation. PLoS ONE 8:e75189

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Busija DW, Gaspar T, Domoki F et al (2008) Mitochondrialmediated suppression of ROS production upon exposure of neurons to lethal stress: mitochondrial targeted preconditioning. Adv Drug Deliv Rev 60:1471–1477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. **e J, Duan L, Qian X et al (2010) K(ATP) channel openers protect mesencephalic neurons against MPP + -induced cytotoxicity via inhibition of ROS production. J Neurosci Res 88:428–437

    Article  CAS  PubMed  Google Scholar 

  15. Takashi E, Wang Y, Ashraf M (1999) Activation of mitochondrial K(ATP) channel elicits late preconditioning against myocardial infarction via protein kinase C signaling pathway. Circ Res 85:1113–1114

    Article  Google Scholar 

  16. Liu D, Lu C, Wan R et al (2002) Activation of mitochondrial ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of Bax translocation and cytochrome c release. J Cereb Blood Flow Metab 22:431–443

    Article  CAS  PubMed  Google Scholar 

  17. Zeng X, Wang T, Jiang L et al (2013) Diazoxide and cyclosporin A protect primary cholinergic neurons against beta-amyloid (1-42)-induced cytotoxicity. Neurol Res 35:529–536

    Article  CAS  PubMed  Google Scholar 

  18. Ma G, Fu Q, Zhang Y et al (2008) Effects of Abeta1-42 on the subunits of KATP expression in cultured primary rat basal forebrain neurons. Neurochem Res 33:1419–1424

    Article  CAS  PubMed  Google Scholar 

  19. Ma G, Gao J, Fu Q et al (2009) Diazoxide reverses the enhanced expression of KATP subunits in cholinergic neurons caused by exposure to Aβ1–42. Neurochem Res 34:2133–2140

    Article  CAS  PubMed  Google Scholar 

  20. Gao HM, Zhou H, Hong JS (2012) NADPH oxidases: novel therapeutic targets for neurodegenerative diseases. Trends Pharmacol Sci 33:295–303

    Article  PubMed Central  PubMed  Google Scholar 

  21. Kadowaki H, Nishitoh H, Urano F et al (2005) Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation. Cell Death Differ 12:19–24

    Article  CAS  PubMed  Google Scholar 

  22. Muthaiyah B, Essa MM, Chauhan V et al (2011) Protective effects of walnut extract against amyloid beta peptide-induced cell death and oxidative stress in PC12cells. Neurochem Res 36:2096–2103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Sponne I, Fifre A, Drouet B et al (2003) Apoptotic neuronal cell death induced by the non-fibrillar amyloid-beta peptide proceeds through an early reactive oxygen species-dependent cytoskeleton perturbation. J Biol Chem 278:3437–3445

    Article  CAS  PubMed  Google Scholar 

  24. Goodman Y, Mattson MP (1996) K+ channel openers protect hippocampal neurons against oxidative injury and amyloid beta-peptide toxicity. Brain Res 706:328–332

    Article  CAS  PubMed  Google Scholar 

  25. Gao HM, Hong JS (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol 29:357–365

    Article  CAS  PubMed  Google Scholar 

  26. Philips T, Robberecht W (2011) Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol 10:253–263

    Article  CAS  PubMed  Google Scholar 

  27. Glass CK (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Coyoy A (2008) Role of NADPH oxidase in the apoptotic death of cultured cerebellar granule neurons. Free Radical Biol Med 45:1056–1064

    Article  CAS  Google Scholar 

  29. Guemez-Gamboa A, Moran J (2009) NOX2 mediates apoptotic death induced by staurosporine but not by potassium deprivation in cerebellar granule neurons. J Neurosci Res 87:2531–2540

    Article  CAS  PubMed  Google Scholar 

  30. Abramov AY (2004) Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24:565–575

    Article  CAS  PubMed  Google Scholar 

  31. Park L (2008) Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci USA 105:1347–1352

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Baines CP, Cohen MV, Downey JM (1999) Signal transduction in ischemic preconditioning: the role of kinases and mitochondrial K(ATP) channels. J Cardiovasc Electrophysiol 10:741–754

    Article  CAS  PubMed  Google Scholar 

  33. Tai KK, McCrossan ZA, Abbott GW (2003) Activation of mitochondrial ATP-sensitive potassium channels increases cell viability against rotenone-induced cell death. J Neurochem 84:1193–1200

    Article  CAS  PubMed  Google Scholar 

  34. Teshima Y, Akao M, Li RA (2003) MitoKATP channel activation protects cerebellar granule neurons from apoptosis induced by oxidative stress. Stroke 34:1796–1802

    Article  CAS  PubMed  Google Scholar 

  35. Dikalov S (2011) Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med 51:1289–1301

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Rey FE, Cifuentes ME, Kiarash A et al (2001) Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(−) and systolic blood pressure in mice. Circ Res 89:408–414

    Article  CAS  PubMed  Google Scholar 

  37. Lee SB, Bae IH, Bae YS et al (2006) Link between mitochondria and NADPH oxidase 1 isozyme for the sustained production of reactive oxygen species and cell death. J Biol Chem 281:36228–36235

    Article  CAS  PubMed  Google Scholar 

  38. Rathore R, Zheng YM, Niu CF et al (2008) Hypoxia activates NADPH oxidase to increase [ROS]i and [Ca2+]i through the mitochondrial ROS-PKCepsilon signaling axis in pulmonary artery smooth muscle cells. Free Radic Biol Med 45:1223–1231

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Irrcher I, Ljubicic V, Hood DA (2009) Interactions between ROS and AMP kinase activity in the regulation of PGC-1alpha transcription in skeletal muscle cells. Am J Physiol Cell Physiol 296:C116–C123

    Article  CAS  PubMed  Google Scholar 

  40. Kim HJ, Park KG, Yoo EK et al (2007) Effects of PGC-1alpha on TNF-alpha-induced MCP-1 and VCAM-1 expression and NF-kappaB activation in human aortic smooth muscle and endothelial cells. Antioxid Redox Signal 9:301–307

    Article  CAS  PubMed  Google Scholar 

  41. Lee C, Miura K, Liu X et al (2000) Biphasic regulation of leukocyte superoxide generation by nitric oxide and peroxynitrite. J Biol Chem 275:38965–38972

    Article  CAS  PubMed  Google Scholar 

  42. Carey RM (2005) Update on the role of the AT2 receptor. Curr Opin Nephrol Hypertens 14:67–71

    Article  CAS  PubMed  Google Scholar 

  43. Dikalova AE, Bikineyeva AT, Budzyn K et al (2010) Therapeutic targeting of mitochondrial superoxide in hypertension. Circ Res 107:106–116

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Ballinger SW (2005) Mitochondrial dysfunction in cardiovascular disease. Free Radic Biol Med 38:1278–1295

    Article  CAS  PubMed  Google Scholar 

  45. Wang L, Zhu QL, Wang GZ et al (2011) The protective roles of mitochondrial ATP-sensitive potassium channels during hypoxiaischemia-reperfusion in brain. Neurosci Lett 491:63–67

    Article  CAS  PubMed  Google Scholar 

  46. Correia SC, Santos RX, Perry G et al (2010) Mitochondria: the missing link between preconditioning and neuroprotection. J Alzheimers Dis 20(Suppl 2):S475–S485

    PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Young Scholars General Program of the National Natural Science Foundation (China, No. 30600202); the International Exchange and Cooperation Program of National Natural Science Foundation (China, No. 30710303072); and the General Program of the National Natural Science Foundation (China, No. 30870874).

Author information

Authors and Affiliations

  1. Department of Neurology, Provincial Hospital Affiliated to Shandong University, **an, Shandong, People’s Republic of China

    Qingxi Fu

  2. Department of Neurology, Linyi People’s Hospital, Linyi, Shandong, 276003, People’s Republic of China

    Qingxi Fu, Naiyong Gao, Jixu Yu, Fumin Wang, Quan** Su & Fengyuan Che

  3. Department of Neurology, Provincial Hospital Affiliated to Shandong University, 324 **gwu Weiqi Road, **an, Shandong, 250021, People’s Republic of China

    Guozhao Ma & Yifeng Du

Authors
  1. Qingxi Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naiyong Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jixu Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guozhao Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yifeng Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fumin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Quan** Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fengyuan Che
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Guozhao Ma or Yifeng Du.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fu, Q., Gao, N., Yu, J. et al. Diazoxide Pretreatment Prevents Aβ1–42 Induced Oxidative Stress in Cholinergic Neurons Via Alleviating NOX2 Expression. Neurochem Res 39, 1313–1321 (2014). https://doi.org/10.1007/s11064-014-1313-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1313-3

Keywords

Search

Navigation