Neuropharmacology

Caspase-1 inhibitor Ac-YVAD-CHO attenuates quinolinic acid-induced increases in p53 and apoptosis in rat striatum

Abstract

Aim:

To study the effects of the caspase-1 inhibitor Ac-YVAD-CHO on quinolinic acid (QA)-induced apoptosis.

Methods:

Rats were pre-treated with intrastriatal infusion of Ac-YVAD-CHO (2-8 μg) before intrastriatal injection of QA (60 nmol). Striatal total proteins, genomic DNA, and nuclear proteins were isolated. The effects of Ac-YVAD-CHO on QA-induced caspase-1 activity, Internucleosomal DNA fragmentation, IκB-α degradation, NF-κB, and AP-1 activation, and increases in p53 protein levels were measured with enzyme assays, agarose gel electrophoresis, electrophoresis mobility shift assays, and Western blot analysis.

Results:

Pre-treatment with Ac-YVAD-CHO inhibited QA-induced Internucleosomal DNA fragmentation. Ac-YVAD-CHO inhibited QA-induced increases in caspase-1 activity and p53 protein levels, but had no effect on QA-induced IκB-α degradation, NF-κB or AP-1 activation.

Conclusion:

Caspase-1 is involved in QA-induced p53 upregulation but not IκB-α degradation. Inhibition of caspase-1 attenuates QA-induced apoptosis in rat striatum.

References

  1. 1

    Zeron MM, Hansson O, Chen N, Wellington CL, Leavitt BR, Brundin P, et al. Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron 2002; 33: 849–60.

  2. 2

    Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA . Apoptosis and necrosis events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell culture. Proc Natl Acad Sci USA 1995; 92: 7162–6.

  3. 3

    Qin ZH, Wang Y, Chase TN . Stimulation of NMDA receptors induces apoptosis in rat brain. Brain Res 1996; 725: 166–76.

  4. 4

    Simonia NA, Getz RL, Leveque JC, Konradi C, Coyle JT . Kainate induces apoptosis in neurons. Neuroscience 1996; 74: 675–83.

  5. 5

    Slack RS, Belliveau DJ, Rosenberg M, Atwal J, Lochmuller H, Aloyz R, et al. Adenovirus-mediated gene transfer of the tumor suppressor, p53, induces apoptosis in postmitotic neurons. J Cell Biol 1996; 135: 1085–96.

  6. 6

    Armstrong RC, Aja TJ, Hoang KD, Gaur S, Bai X, Alnemri ES, et al. Activation of the CED3/ICE-related protease CPP32 in cerebellar granule neurons undergoing apoptosis but not necrosis. J Neurosci 1997; 17: 553–62.

  7. 7

    Eldadah BA, Yakovlev A, Faden AI . The role of CED-3-related cysteine proteases in apoptosis of cerebellar granule cells. J Neurosci 1997; 17: 6105–13.

  8. 8

    Jordan J, Galino MF, Prehn JHM, Weichselbaum RR, Beckett M, Ghadge GD, et al. p53 expression induces apoptosis in hippocampal pyramidal neurons cultures. J Neurosci 1997; 17: 1397–405.

  9. 9

    Sakhi S, Bruce A, Sun N, Tocco G, Baudry M, Schreiber SS . p53 induction is associated with neuronal damage in the central nervous system. Proc Natl Acad Sci USA 1994; 91: 7525–9.

  10. 10

    Hughes PE, Alexi T, Yoshida T, Schreiber SS, Knusel B . Excitotoxic lesion of rat brain with quinolinic acid induces expression of p53 messenger RNA and protein and p53-inducible genes Bax and GADD-45 in brain areas showing DNA fragmentation. Neuroscience 1997; 74: 1143–60.

  11. 11

    Du Y, Bales KR, Dodel RC, Hamilton-Byrd E, Horn JW, Czilli DL, et al. Activation of a caspase 3-related cysteine protease is required for glutamate-mediated apoptosis of cultured cerebellar granule neurons. Proc Natl Acad Sci USA 1997; 94: 11657–62.

  12. 12

    Guerrini L, Blasi F, Denis-Donini S . Synaptic activation of NF-κB by glutamate in cerebellar granule neurons in vitro. Proc Natl Acad Sci USA 1995; 92: 9077–81.

  13. 13

    Kaltschmidt C, Kaltschmidt B, Baeuerle PA . Stimulation of ionotropic glutamate receptors activate transcription factor NF-κB in primary neurons. Proc Natl Acad Sci USA 1995; 92: 9618–22.

  14. 14

    Qin ZH, Wang Y, Nakai M, Chase TN . Nuclear factor-κB contributes to excitotoxin-induced apoptosis. Mol Pharmacol 1998; 53: 33–42.

  15. 15

    Nakai M, Qin ZH, Chen JF, Wang Y, Chase TN . Kanic acidinduced apoptosis is associated with NF-κB activation. J Neurochem 1999; 74: 647–58.

  16. 16

    Qin ZH, Chen RW, Wang Y, Nakai M, Chuang DM, Chase TN . NF-κB nuclear translocation up-regulates c-Myc and p53 during N-methyl-D-aspartate receptor-mediated apoptosis. J Neurosci 1999; 19: 4023–33.

  17. 17

    Aleyasin H, Cregan SP, Iyirhiaro G, O'Hare MJ, Callaghan SM, Slack RS, et al. Nuclear factor-κB modulates the p53 response in neurons exposed to DNA damage. J Neurosci 2004; 24: 2963–73.

  18. 18

    Nakai M, Qin Z-H, Wang Y, Chase TN . NMDA and non-NMDA receptor-stimulated IκB-α degradation: differential effects of the caspase-3 inhibitor DEVD.CHO, free radical scanvenger OPC14117 and ethanol. Brain Res 2000; 859: 207–16.

  19. 19

    Qin ZH, Wang Y, Chase TN . A caspase-3-like protease is involved in NF-κB activation induced by stimulation of N-methyl-D-aspartate receptors in rat striatum. Mol Brain Res 2000; 80: 111–22.

  20. 20

    Grilli M, Memo M . Possible role of NF-κB and p53 in the glutamate-induced pro-apoptotic neuronal pathway. Cell Death Differ 1999; 6: 22–7.

  21. 21

    Levine AJ . p53, the cellular gatekeeper for growth and division. Cell 1997; 88: 323–31.

  22. 22

    Wu H, Lozano G . NF-κB activation of p53: a potential mechanism for supressing cell growth in response to stress. J Biol Chem 1994; 269: 20067–74.

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Author information

Correspondence to Zheng-hong Qin.

Additional information

Project supported by the National Natural Science Foundation of China (No 30370506).

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Keywords

  • caspase 1
  • Ac-YVAD-CHO
  • Huntington disease
  • protein p53
  • NF-kappaB inhibitor alpha
  • apoptosis
  • NF-kappaB

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