title: Caspase-3 mediates hippocampal apoptosis in pneumococcal meningitis.
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-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.
authors.affiliation: Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, 3010 Bern, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Gianinazzi
authors.forename: Denis
authors.initials: D
authors.lastname: Grandgirard
authors.forename: Hans
authors.initials: H
authors.lastname: Imboden
authors.forename: Lotti
authors.initials: L
authors.lastname: Egger
authors.forename: Damian N
authors.initials: DN
authors.lastname: Meli
authors.forename: Yoeng-Delphine
authors.initials: YD
authors.lastname: Bifrare
authors.forename: Philipp C
authors.initials: PC
authors.lastname: Joss
authors.forename: Martin G
authors.initials: MG
authors.lastname: Täuber
authors.forename: Christoph
authors.initials: C
authors.lastname: Borner
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Leib
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001835:Body Weight; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism; D003374:Coumarins / Q000008:administration & dosage; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling / Q000379:methods; D007375:Interleukin-1; D008586:Meningitis, Pneumococcal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage; D011008:Pneumococcal Infections; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
chemical_list: C112287:Ac-aspartyl-glutamyl-valyl-aspartyl-aminomethylcoumarin; D016229:Amyloid beta-Peptides; D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; C418606:neugrin; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases