Caspase-3 mediates hippocampal apoptosis in pneumococcal meningitis

Gianinazzi, Christian; Grandgirard, Denis; Imboden, Hans; Egger, Lotti; Meli, Damian N; Bifrare, Yoeng-Delphine; Joss, Philipp; Täuber, Martin G.; Borner, Christoph; Leib, Stephen (2003). Caspase-3 mediates hippocampal apoptosis in pneumococcal meningitis. Acta neuropathologica, 105(5), pp. 499-507. Springer 10.1007/s00401-003-0672-7

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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-beta 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-alpha and IL-1beta concentrations in the cerebrospinal fluid space. Taken together, the present results identify caspase-3 as a key effector of neuronal apoptosis in pneumococcal meningitis.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Infectiology
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases
08 Faculty of Science > Department of Biology > Institute of Cell Biology
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research

UniBE Contributor:

Grandgirard, Denis; Imboden, Hans; Joss, Philipp; Täuber, Martin G. and Leib, Stephen

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

0001-6322

Publisher:

Springer

Language:

English

Submitter:

Stephen Leib

Date Deposited:

01 Sep 2014 08:41

Last Modified:

08 Jul 2015 10:18

Publisher DOI:

10.1007/s00401-003-0672-7

PubMed ID:

12677451

Web of Science ID:

000182702400012

BORIS DOI:

10.7892/boris.52745

URI:

https://boris.unibe.ch/id/eprint/52745 (FactScience: 60820)

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