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Caspase-3 mediates hippocampal apoptosis in pneumococcal meningitis

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Abstract

Bacterial meningitis causes neuronal apoptosis in the hippocampal dentate gyrus, which is associated with learning and memory impairments after cured disease. The execution of the apoptotic program involves pathways that converge on activation of caspase-3, which is required for morphological changes associated with apoptosis. Here, the time course and the role of caspase-3 in neuronal apoptosis was assessed in an infant rat model of pneumococcal meningitis. During clinically asymptotic meningitis (0–12 h after infection), only minor apoptotic damage to the dentate gyrus was observed, while the acute phase (18–24 h) was characterized by a massive increase of apoptotic cells, which peaked at 36 h. In the subacute phase of the disease (36–72 h), the number of apoptotic cells decreased to control levels. Enzymatic caspase-3 activity was significantly increased in hippocampal tissue of infected animals compared to controls at 22 h. The activated enzyme was localized to immature cells of the dentate gyrus, and in vivo activity was evidenced by cleavage of the amyloid-β precursor protein. Intracisternal administration of the caspase-3-specific inhibitor Ac-DEVD-CHO significantly reduced apoptosis in the hippocampal dentate gyrus. In contrast to a study where the decrease of hippocampal apoptosis after administration of a pan-caspase inhibitor was due to downmodulation of the inflammatory response, our data demonstrate that specific inhibition of caspase-3 did not affect inflammation assessed by TNF-α and IL-1β concentrations in the cerebrospinal fluid space. Taken together, the present results identify caspase-3 as a key effector of neuronal apoptosis in pneumococcal meningitis.

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Acknowledgements

We greatly acknowledge Dr. D. Nicholson (Merck Frosst Canada & Co.; ΔC-APP antibody), and Dr. A. Srinivasan (Idun Pharmaceuticals; CM 1 antibody) for supporting this work. We thank Franziska Simon, Andreas Messerli and Oliver Schütz for excellent technical support. This work was supported by grants from the Swiss National Science Foundation (32-61654.00 and 632-66057.01), the Meningitis Research Foundation (14/00), and the NIH (NS-35902).

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Authors and Affiliations

  1. Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, 3010, Bern, Switzerland

    Christian Gianinazzi, Denis Grandgirard, Damian N. Meli, Yoeng-Delphine Bifrare, Philipp C. Joss, Martin G. Täuber & Stephen L. Leib

  2. Institute for Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany

    Lotti Egger & Christoph Borner

  3. Department of Neurobiology, University of Bern, Bern, Switzerland

    Hans Imboden

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  1. Christian Gianinazzi
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Correspondence to Stephen L. Leib.

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Gianinazzi, C., Grandgirard, D., Imboden, H. et al. Caspase-3 mediates hippocampal apoptosis in pneumococcal meningitis. Acta Neuropathol 105, 499–507 (2003). https://doi.org/10.1007/s00401-003-0672-7

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