Skip to main content

Advertisement

Springer Nature Link
Log in

Expression of Bcl-2, Bax and Caspase-3 in Nerve Tissues of Rats Chronically Exposed to 2,5-hexanedione

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

Abstract

Occupational exposure and experimental intoxication with n-hexane or its metabolite 2,5-hexanedione (HD) produce a central-peripheral neuropathy. However, the mechanism remains unknown. We hypothesized that HD affected the expression of Bcl-2, Bax and Caspase-3 in the central nervous system (CNS) and the peripheral nervous system (PNS). Male adult Wistar rats were administered by intraperitoneal injection at a dosage of 200 or 400 mg/kg HD, five days per week for 8 weeks. Samples of the cerebral cortex, cerebellum, spinal cord and sciatic nerves were collected and examined for Bcl-2, Bax and Caspase-3 expression using Western blotting. Subchronic exposure to HD resulted in significantly increased expression of both anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bax and Caspase-3 in cerebral cortex and cerebellum, which exhibited a dose-dependent pattern. Though little change was detected in spinal cord, our results showed that the expression of Bcl-2, Bax and Caspase-3 was markedly enhanced in the sciatic nerves. These findings suggested that the changes of apoptosis-related protein level in rat nerve tissues were associated with the intoxication of HD, which might be involved in early molecular regulatory mechanism of apoptosis in the HD-induced neuropathy.

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

Similar content being viewed by others

References

  1. Spencer PS, Schaumburg HH (1977) Neurotoxic properties of certain aliphatic hexacarbons. Proc R Soc Med 70:37–38

    PubMed  CAS  Google Scholar 

  2. Couri D, Milks M (1982) Toxicity and metabolism of the neurotoxic hexacarbons n-hexane, 2-hexanone, and 2,5-hexanedione. Ann Rev Pharmacol Toxicol 22:145–166

    Article  CAS  Google Scholar 

  3. Graham DG, Amarnath V, Valentine WM et al (1995) Pathogenetic studies of hexane and carbon disulfide neurotoxicity. Crit Rev Toxicol 25:91–112

    PubMed  CAS  Google Scholar 

  4. Lehning EJ, Jortner BS, Fox JH et al (2000) gamma-diketone peripheral neuropathy. I. Quality morphometric analyses of axonal atrophy and swelling. Toxicol Appl Pharmacol 165(2):127–140

    Article  PubMed  CAS  Google Scholar 

  5. Sterman AB, Sposito N (1985) 2,5-Hexanedione and acrylamide produce reorganization of motoneuron perikarya. Neuropathol Appl Neurobiol 11(3):201–212

    PubMed  CAS  Google Scholar 

  6. Sterman AB (1982) Cell body remodeling during dying-back axonopathy: DRG changes during advanced disease. J Neuropathol Exp Neurol 41(4):400–411

    PubMed  CAS  Google Scholar 

  7. Moretto G, Monaco S, Passarin MG et al (1991) Cytoskeletal changes induced by 2,5-hexanedione on developing human neurons in vitro. Arch Toxicol 65(5):409–413

    Article  PubMed  CAS  Google Scholar 

  8. Carney R, Dardis C, Cullen WK et al (2002) Early spatial memory deficit induced by 2,5-hexanedione in the rat. Toxicol Lett 128(1–3):107–115

    Article  PubMed  CAS  Google Scholar 

  9. De Rojas TC, Goldstein BD (1990) Lack of evidence for the size principle of selective vulnerability of axons in toxic neuropathies. I. The effects of subcutaneous injections of 2,5-hexanedione on behavior and muscle spindle function. Toxicol Appl Pharmacol 104(1):47–58

    Article  PubMed  Google Scholar 

  10. Mateus ML, dos Santos AP, Batoreu MC (2002) Evidence of zinc protection against 2,5-hexanedione neurotoxicity: correlation of neurobehavioral testing with biomarkers of excretion. Neurotoxicology 23(6):747–754

    Article  PubMed  CAS  Google Scholar 

  11. Ogawa Y, Shimizu H, Kim SU (1996) 2,5-Hexanedione induced apoptosis in cultured mouse DRG neurons. Int Arch Occup Environ Health 68:495–497

    PubMed  CAS  Google Scholar 

  12. Strange P, Moller A, Ladefoged O et al (1991) Total number and mean cell volume of neocortical neurons in rats exposed to 2,5-hexanedione with and without acetone. Neurotoxicol Teratol 13(4):401–406

    Article  PubMed  CAS  Google Scholar 

  13. Backstrom B, Dumanski JP, Collins VP (1990) The effects of 2,5-hexanedione on the retina of albino rats. Neurotoxicology 11(1):47–55

    PubMed  CAS  Google Scholar 

  14. Cavanagh JB (1964) The significance of the “dying back” process in experimental and human neurological disease. Int Rev Exp Pathol 3:219–267

    PubMed  CAS  Google Scholar 

  15. Lo AC, Houenou LJ, Oppenheim RW (1995) Apoptosis in the nervous system: morphological features, methods, pathology, and prevention. Arch Histol Cytol 58(2):139–149

    PubMed  CAS  Google Scholar 

  16. Sima AA, Bouchier M, Christensen H (1983) Axonal atrophy in sensory nerves of the diabetic BB-Wistar rat: a possible early correlate of human diabetic neuropathy. Ann Neurol 13(3):264–272

    Article  PubMed  CAS  Google Scholar 

  17. Canesi M, Perbellini L, Maestri L et al (2003) Poor metabolization of n-hexane in Parkinson’s disease. J Neurol 250(5):556–560

    Article  PubMed  CAS  Google Scholar 

  18. Jenner P (1998) Oxidative mechanisms in nigral cell death in Parkinson’s disease. Mov Disord 13(Suppl 1):24–34

    PubMed  Google Scholar 

  19. Jellinger KA (2001) Cell death mechanisms in neurodegeneration. J Cell Mol Med 5(1):1–17

    Article  PubMed  CAS  Google Scholar 

  20. Lopez E, Pozas E, Rivera R et al (1999) Bcl-2, Bax and Bcl-x expression following kainic acid administration at convulsant doses in the rat. Neuroscience 91(4):1461–1470

    Article  PubMed  CAS  Google Scholar 

  21. Laemmli UK et al (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227(5259):680–685

    Article  PubMed  CAS  Google Scholar 

  22. Zha H, Aime-Sempe C, Sato T et al (1996) Proapoptotic protein Bax heterodimerizes with Bcl-2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH1 and BH2. J Biol Chem 271(13):7440–7444

    Article  PubMed  CAS  Google Scholar 

  23. Garcia I, Martinou I, Tsujimoto Y et al (1992) Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene. Science 258(5080):302–304

    Article  PubMed  CAS  Google Scholar 

  24. Kane DJ, Sarafian TA, Anton R et al (1993) Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science 262(5137):1274–1277

    Article  PubMed  CAS  Google Scholar 

  25. Chen RW, Chuang DM (1999) Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem 274:6039–6042

    Article  PubMed  CAS  Google Scholar 

  26. Wei H, Leeds P, Chen RW et al (2000) Neuronal apoptosis induced by pharmacological concentrations of 3-hydroxykynurenine: characterization and protection by dantrolene and Bcl-2 overexpression. J Neurochem 75(1):81–90

    Article  PubMed  CAS  Google Scholar 

  27. Marshall KA, Daniel SE, Cairns N et al (1997) Upregulation of the anti-apoptotic protein Bcl-2 may be an early event in neurodegeneration: studies on Parkinson’s and incidental Lewy body disease. Biochem Biophys Res Commun 240(1):84–87

    Article  PubMed  CAS  Google Scholar 

  28. Mogi M, Harada M, Kondo T et al (1996) Bcl-2 protein is increased in the brain from Parkinsonian patients. Neurosci Lett 215(2):137–139

    PubMed  CAS  Google Scholar 

  29. Satou T, Cummings BJ, Cotman CW (1995) Immunoreactivity for Bcl-2 protein within neurons in the Alzheimer’s disease brain increases with disease severity. Brain Res 697(1–2):35–43

    Article  PubMed  CAS  Google Scholar 

  30. Kitamura Y, Shimohama S, Kamoshima W et al (1998) Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer’s disease. Brain Res 780(2):260–269

    Article  PubMed  CAS  Google Scholar 

  31. Fan H, Favero M, Vogel MW (2001) Elimination of Bax expression in mice increases cerebellar purkinje cell numbers but not the number of granule cells. J Comp Neurol 436(1):82–91

    Article  PubMed  CAS  Google Scholar 

  32. Deckwerth TL, Elliott JL, Knudson CM et al (1996) BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17(3):401–411

    Article  PubMed  CAS  Google Scholar 

  33. White FA, Keller-Peck CR, Knudson CM et al (1998) Widespread elimination of naturally occurring neuronal death in Bax-deficient mice. J Neurosci 18(4):1428–1439

    PubMed  CAS  Google Scholar 

  34. Kaufmann SH, Desnoyers S, Ottaviano Y et al (1993) Specific proteolytic cleavage of poly (ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res 53(17):3976–3985

    PubMed  CAS  Google Scholar 

  35. Sastry PS, Rao KS (2000) Apoptosis and the nervous system. J Neurochem 74(1):1–20

    Article  PubMed  CAS  Google Scholar 

  36. Jellinger KA, Stadelmann CH (2000) The enigma of cell death in neurodegenerative disorders. J Neural Transm Suppl 60:21–36

    PubMed  Google Scholar 

  37. MacGibbon GA, Lawlor PA, Walton M et al (1997) Expression of Fos, Jun, and Krox family proteins in Alzheimer’s disease. Exp Neurol 147(2):316–332

    Article  PubMed  CAS  Google Scholar 

  38. Stadelmann C, Bruck W, Bancher C et al (1998) Alzheimer disease: DNA fragmentation indicates increased neuronal vulnerability, but not apoptosis. J Neuropathol Exp Neurol 57(5):456–464

    Article  PubMed  CAS  Google Scholar 

  39. Torp R, Su JH, Deng G et al (1998) GADD45 is induced in Alzheimer’s disease, and protects against apoptosis in vitro. Neurobiol Dis 5(4):245–252

    Article  PubMed  CAS  Google Scholar 

  40. Anderson AJ, Stoltzner S, Lai F et al (2000) Morphological and biochemical assessment of DNA damage and apoptosis in Down syndrome and Alzheimer disease, and effect of postmortem tissue archival on TUNEL. Neurobiol Aging 21(4):511–524

    Article  PubMed  CAS  Google Scholar 

  41. Hartmann A, Hunot S, Michel PP et al (2000) Caspase-3: a vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci USA 97(6):2875–2880

    Article  PubMed  CAS  Google Scholar 

  42. Jellinger KA (2000) Cell death mechanisms in Parkinson’s disease. J Neural Transm 107(1):1–29

    Article  PubMed  CAS  Google Scholar 

  43. Vukosavic S, Dubois-Dauphin M, Romero N et al (1999) Bax and Bcl-2 interaction in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem 73(6):2460–2468

    Article  PubMed  CAS  Google Scholar 

  44. Merry DE, Korsmeyer SJ (1997) Bcl-2 gene family in the nervous system. Annu Rev Neurosci 20:245–267

    Article  PubMed  CAS  Google Scholar 

  45. Keane RW, Srinivasan A, Foster LM et al (1997) Activation of CPP32 during apoptosis of neurons and astrocytes. J Neurosci Res 48(2):168–180

    Article  PubMed  CAS  Google Scholar 

  46. Chen J, Nagayama T, Jin K et al (1998) Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci 18(13):4914–4928

    PubMed  CAS  Google Scholar 

  47. Ni B, Wu X, Su Y et al (1998) Transient global forebrain ischemia induces a prolonged expression of the caspase-3 mRNA in rat hippocampal CA1 pyramidal neurons. J Cereb Blood Flow Metab 18(3):248–256

    Article  PubMed  CAS  Google Scholar 

  48. Ladefoged O, Roswall K, Larsen JJ et al (1994) Acetone potentiation and influence on the reversibility of 2,5-hexanedione-induced neurotoxicity studied with behavioural and morphometric methods in rats. Pharmacol Toxicol 74(4–5):294–299

    PubMed  CAS  Google Scholar 

  49. Sager PR (1989) Cytoskeletal effects of acrylamide and 2,5-hexanedione: selective aggregation of vimentin filaments. Toxicol Appl Pharmacol 97(1):141–155

    Article  PubMed  CAS  Google Scholar 

  50. Powell HC, Koch T, Garrett R et al (1978) Schwann cell abnormalities in 2,5-hexanedione neuropathy. J Neurocytol 7(4):517–528

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Ministry of Science and Technology of China (No. 2002CB512907), and National Natural Science Foundation of China (No. 30271138).

Author information

Authors and Affiliations

  1. Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, P.R. China

    Ning Cui, Shanxia Li, Xiulan Zhao, Tianliang Zhang, Cuili Zhang, Lihua Yu, Zhengping Zhu & Keqin Xie

  2. College of Basic Medical Sciences, Shandong University of Traditional Chinese Medicine, 53 Jingshi Road, Jinan, Shandong, 250014, P.R. China

    Ning Cui

  3. Institute for Health Inspection and Supervision, Weihai, Shandong, 264200, P.R. China

    Shanxia Li

Authors
  1. Ning Cui
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Shanxia Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Xiulan Zhao
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Tianliang Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Cuili Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Lihua Yu
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Zhengping Zhu
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Keqin Xie
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Keqin Xie.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cui, N., Li, S., Zhao, X. et al. Expression of Bcl-2, Bax and Caspase-3 in Nerve Tissues of Rats Chronically Exposed to 2,5-hexanedione. Neurochem Res 32, 1566–1572 (2007). https://doi.org/10.1007/s11064-007-9359-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-007-9359-0

Keywords