Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Neuroprotection by a caspase inhibitor in acute bacterial meningitis

Abstract

Half of the survivors of bacterial meningitis experience motor deficits, seizures, hearing loss or cognitive impairment, despite adequate bacterial killing by antibiotics. We demonstrate that the broad-spectrum caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone (z-VAD-fmk) prevented hippocampal neuronal cell death and white blood cell influx into the cerebrospinal fluid compartment in experimental pneumococcal meningitis. Hippocampal neuronal death was due to apoptosis derived from the inflammatory response in the cerebrospinal fluid. Apoptosis was induced in vitro in human neurons by inflamed cerebrospinal fluid and was blocked by z-VAD-fmk. As apoptosis drives neuronal loss in pneumococcal meningitis, caspase inhibitors might provide a new therapeutic option directed specifically at reducing brain damage.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Induction of neuronal apoptosis in rabbit meningitis and its inhibition by z-VAD-fmk.
Figure 2: Effects of anti-apoptotic and anti-leukocyte treatment on hippocampal neuronal apoptosis and CSF leukocytosis after 24 hours pneumococcal meningitis.
Figure 3: Immunohistochemical detection of active caspase-3 in the dentate gyrus after 24 h of pneumococcal meningitis.
Figure 4: Effects of z-VAD-fmk on neuronal damage 6 d after induction of pneumococcal meningitis.
Figure 5: Pneumococcal-induced hippocampal neuronal injury is mediated by the host inflammatory response.
Figure 6: Induction of apoptosis of human cortical neurons by infected CSF is inhibited by z-VAD-fmk.
Figure 7: Quantification of apoptotic and necrotic human neurons by acridine orange/ethidium bromide staining.

Similar content being viewed by others

References

  1. Schuchat, A. et al. Bacterial meningitis in the United States in 1995. N. Engl. J. Med. 337, 970–976 (1997).

    Article  CAS  Google Scholar 

  2. Quagliarello, V. & Scheld, W.M. Bacterial meningitis: pathogenesis, pathophysiology, and progress. N. Engl. J. Med. 327, 864–872 (1992).

    Article  CAS  Google Scholar 

  3. Saez-Llorens, X., Ramilo, O., Mustafa, M.M., Mertsola, J. & McCracken Jr., G.H. Molecular pathophysiology of bacterial meningitis: Current concepts and therapeutic implications. J. Pediatr. 116, 671–684 (1990).

    Article  CAS  Google Scholar 

  4. Tuomanen, E.I., Saukkonen, K., Sande, S., Cioffe, C. & Wright, S.D. Reduction of inflammation, tissue damage, and mortality in bacterial meningitis in rabbits treated with monoclonal antibodies against adhesion-promoting receptors of leukocytes. J. Exp. Med. 170, 959–969 (1989).

    Article  CAS  Google Scholar 

  5. Saukkonen, K. et al. The role of cytokines in the generation of inflammation and tissue damage in experimental gram-positive meningitis. J. Exp. Med. 171, 439–448 ( 1990).

    Article  CAS  Google Scholar 

  6. Zysk, G. et al. Anti-inflammatory treatment influences neuronal apoptotic cell death in the dentate gyrus in experimental pneumococcal meningitis. J. Neuropathol. Exp. Neurol. 55, 722– 728 (1996).

    Article  CAS  Google Scholar 

  7. Leib, S.L., Kim, Y.S., Chow, L.L., Sheldon, R.A. & Tauber, M.G. Reactive oxygen intermediates contribute to necrotic and apoptotic neuronal injury in an infant rat model of bacterial meningitis due to group B streptococci. J. Clin. Invest. 98, 2632–2639 (1996).

    Article  CAS  Google Scholar 

  8. Linnik, M.D., Zobrist, R.H. & Hatfield, M.D. Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke 24, 2002–2009 (1993).

    Article  CAS  Google Scholar 

  9. Tauber, M.G., Kim, Y.S. & Leib, S.L. in In Defense of the Brain: Current Concepts in the Immunopathogenesis and Clinical Aspects of CNS Infections (eds. Peterson, P.K. & Remington, J.S.) 125–143 (Blackwell Science, Malden, Massachusetts, 1997).

    Google Scholar 

  10. Cohen, G.M. Caspases: the executioners of apoptosis. Biochem. J. 326, 1–16 (1997).

    Article  CAS  Google Scholar 

  11. Milligan, C.E. et al. Peptide inhibitors of the ICE protease family arrest programmed cell death of motoneurons in vivo and in vitro. Neuron 15, 385–393 ( 1995).

    Article  CAS  Google Scholar 

  12. Braun, J.S. & Tuomanen, E.I. Molecular mechanisms of brain damage in bacterial meningitis. Adv. Pediatr. Infect. Dis. 14, 49–72 (1998).

    Google Scholar 

  13. Tauber, M.G. & Zwahlen, A. Animal models for meningitis. Methods Enzymol. 235, 93–106 (1994).

    Article  CAS  Google Scholar 

  14. Dodel, R.C. et al. Peptide inhibitors of caspase-3-like proteases attenuate 1-methyl-4-phenylpyridinum-induced toxicity of cultured fetal rat mesencephalic dopamine neurons. Neuroscience 86, 701– 707 (1998).

    Article  CAS  Google Scholar 

  15. Pronk, G.J., Ramer, K., Amiri, P. & Williams, L.T. Requirement of an ICE-like protease for induction of apoptosis and ceramide generation by REAPER. Science 271, 808– 810 (1996).

    Article  CAS  Google Scholar 

  16. Slee, E.A. et al. Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK) inhibits apoptosis by blocking the processing of CPP32. Biochem. J. 315, 21–24 ( 1996).

    Article  CAS  Google Scholar 

  17. Chen, Y. & Zychlinsky, A. Apoptosis induced by bacterial pathogens. Microb. Pathog. 17, 203– 212 (1994).

    Article  CAS  Google Scholar 

  18. Zychlinsky, A., Prevost, M.C. & Sansonetti, P.J. Shigella flexneri induces apoptosis in infected macrophages. Nature 358, 167– 169 (1992).

    Article  CAS  Google Scholar 

  19. Zychlinsky, A. & Sansonetti, P. Apoptosis in bacterial pathogenesis. J. Clin. Invest. 100, 493–496 (1997).

    Article  CAS  Google Scholar 

  20. Tauber, M.G., Sachdeva, M., Kennedy, S.L., Loetscher, H. & Lesslauer, W. Toxicity in neuronal cells caused by cerebrospinal fluid from pneumococcal and gram-negative meningitis. J. Infect. Dis. 166, 1045–1050 (1992).

    Article  CAS  Google Scholar 

  21. Hara, H. et al. Inhibition of interleukin 1β converting enzyme family proteases reduces ischemic and exitotoxic neuronal damage. Proc. Natl. Acad. Sci. USA 94, 2007–2012 ( 1997).

    Article  CAS  Google Scholar 

  22. Auer, R.N. & Siesjo, B.K. Biological differences between ischemia, hypoglycemia, and epilepsy. Ann. Neurol. 24, 699–707 (1988).

    Article  CAS  Google Scholar 

  23. Leib, S.L., Kim, Y.S., Ferriero, D.M. & Tauber, M.G. Neuroprotective effect of excitatory amino acid antagonist kynurenic acid in experimental bacterial meningitis. J. Infect. Dis. 173, 166–171 (1996).

    Article  CAS  Google Scholar 

  24. Roos, K.L., Tunkel, A.R. & Scheld, W.M. in Infections of the Central Nervous System. (eds. Scheld, W.M., Whitley, R.J. & Durack, D.T.) 335– 401 (Lippincott-Raven, Philadelphia, 1997).

    Google Scholar 

  25. Ankarcrona, M. et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15, 961–973 (1995).

    Article  CAS  Google Scholar 

  26. Eichhold, T., Hookfin, E., Taiwo, Y., De, B. & Wehmeyer, K. Isolation and quantification of fluoroacetate in rat tissues, following dosing of Z-Phe-Ala-CH2-F, a peptidyl fluoromethyl ketone protease inhibitor. J. Pharm. Biomed. Anal. 16, 459 –467 (1997).

    Article  CAS  Google Scholar 

  27. Ronnett, G.V., Hester, L.D., Nye, J.S. & Snyder, S.H. Human cerebral cortical cell lines from patients with unilateral megalencephaly and Rasmussen's encephalitis. Neuroscience 63, 1081– 1099 (1994).

    Article  CAS  Google Scholar 

  28. Lacks, S.A. & Hotchkiss, R.D. A study of the genetic material determining an enzyme activity in pneumococcus. Biochim. Biophys. Acta 39, 508–517 ( 1960).

    Article  CAS  Google Scholar 

  29. Pitrak, D.L., Tsai, H.C., Mullane, K.M., Sutton, S.H. & Stevens, P. Accelerated neutrophil apoptosis in the acquired immunodeficiency syndrome. J. Clin. Invest. 98, 2714–2719 (1996).

    Article  CAS  Google Scholar 

  30. Gavrieli, Y., Sherman, Y. & Ben-Sasson, S.A. Identification of programmed cell death in situ via specific labelling of nuclear DNA fragmentation. J. Cell Biol. 119, 493–501 ( 1992).

    Article  CAS  Google Scholar 

  31. Evers, P., Uylings, H.B.M. & Suurmeijer, A.J.H. Antigen retrieval in formaldehyde-fixed human brain tissue. Methods 15, 133– 140 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the technicians of the Department of Pathology of St. Jude Children's Research Hospital for assistance, T. Mandrell for advice and help with the rabbit brain perfusion and C. Eischen for her thoughts and advice. This work was supported by AI 27913 (E.I.T.), CA 76379 (J.L.C.), Cancer Center Support CORE grant P30 CA21765 and by the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to E.I. Tuomanen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Braun, J., Novak, R., Herzog, KH. et al. Neuroprotection by a caspase inhibitor in acute bacterial meningitis . Nat Med 5, 298–302 (1999). https://doi.org/10.1038/6514

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/6514

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing