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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Schuchat, A. et al. Bacterial meningitis in the United States in 1995. N. Engl. J. Med. 337, 970–976 (1997).
Quagliarello, V. & Scheld, W.M. Bacterial meningitis: pathogenesis, pathophysiology, and progress. N. Engl. J. Med. 327, 864–872 (1992).
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).
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).
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).
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).
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).
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).
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).
Cohen, G.M. Caspases: the executioners of apoptosis. Biochem. J. 326, 1–16 (1997).
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).
Braun, J.S. & Tuomanen, E.I. Molecular mechanisms of brain damage in bacterial meningitis. Adv. Pediatr. Infect. Dis. 14, 49–72 (1998).
Tauber, M.G. & Zwahlen, A. Animal models for meningitis. Methods Enzymol. 235, 93–106 (1994).
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).
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).
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).
Chen, Y. & Zychlinsky, A. Apoptosis induced by bacterial pathogens. Microb. Pathog. 17, 203– 212 (1994).
Zychlinsky, A., Prevost, M.C. & Sansonetti, P.J. Shigella flexneri induces apoptosis in infected macrophages. Nature 358, 167– 169 (1992).
Zychlinsky, A. & Sansonetti, P. Apoptosis in bacterial pathogenesis. J. Clin. Invest. 100, 493–496 (1997).
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).
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).
Auer, R.N. & Siesjo, B.K. Biological differences between ischemia, hypoglycemia, and epilepsy. Ann. Neurol. 24, 699–707 (1988).
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).
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).
Ankarcrona, M. et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15, 961–973 (1995).
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).
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).
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).
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).
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).
Evers, P., Uylings, H.B.M. & Suurmeijer, A.J.H. Antigen retrieval in formaldehyde-fixed human brain tissue. Methods 15, 133– 140 (1998).
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
Corresponding author
Rights 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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/6514
This article is cited by
-
Caspr1 is a host receptor for meningitis-causing Escherichia coli
Nature Communications (2018)
-
Resveratrol Acts Anti-Inflammatory and Neuroprotective in an Infant Rat Model of Pneumococcal Meningitis by Modulating the Hippocampal miRNome
Molecular Neurobiology (2018)
-
Infectious immunity in the central nervous system and brain function
Nature Immunology (2017)
-
Role of purinergic signaling in experimental pneumococcal meningitis
Scientific Reports (2017)
-
Community-acquired bacterial meningitis
Nature Reviews Disease Primers (2016)