Abstract
Streptococcus pneumoniae is the most common pathogen causing non-epidemic bacterial meningitis worldwide. The immune response and inflammatory processes contribute to the pathophysiology. Hence, the anti-inflammatory dexamethasone is advocated as adjuvant treatment although its clinical efficacy remains a question at issue. In experimental models of pneumococcal meningitis, dexamethasone increased neuronal damage in the dentate gyrus. Here, we investigated expressional changes in the hippocampus and cortex at 72 h after infection when dexamethasone was given to infant rats with pneumococcal meningitis. Nursing Wistar rats were intracisternally infected with Streptococcus pneumoniae to induce experimental meningitis or were sham-infected with pyrogen-free saline. Besides antibiotics, animals were either treated with dexamethasone or saline. Expressional changes were assessed by the use of GeneChip® Rat Exon 1.0 ST Arrays and quantitative real-time PCR. Protein levels of brain-derived neurotrophic factor, cytokines and chemokines were evaluated in immunoassays using Luminex xMAP® technology. In infected animals, 213 and 264 genes were significantly regulated by dexamethasone in the hippocampus and cortex respectively. Separately for the cortex and the hippocampus, Gene Ontology analysis identified clusters of biological processes which were assigned to the predefined categories “inflammation”, “growth”, “apoptosis” and others. Dexamethasone affected the expression of genes and protein levels of chemokines reflecting diminished activation of microglia. Dexamethasone-induced changes of genes related to apoptosis suggest the downregulation of the Akt-survival pathway and the induction of caspase-independent apoptosis. Signalling of pro-neurogenic pathways such as transforming growth factor pathway was reduced by dexamethasone resulting in a lack of pro-survival triggers. The anti-inflammatory properties of dexamethasone were observed on gene and protein level in experimental pneumococcal meningitis. Further dexamethasone-induced expressional changes reflect an increase of pro-apoptotic signals and a decrease of pro-neurogenic processes. The findings may help to identify potential mechanisms leading to apoptosis by dexamethasone in experimental pneumococcal meningitis.
Highlights
Treatment of bacterial meningitis (BM) with sulfonamids was successfully introduced in the 1930’s and the advent of third generation cephalosporins further reduced the mortality rates [1]
Histopathological assessments in experimental models as well as autopsy cases showed three forms of injury in the central nervous system: apoptosis occurs in the hippocampal dentate gyrus, necrosis is found in the cerebral cortex, and loss of type 1 neurons in the spiral ganglion
We detected diminished expression of genes involved in the activation and migration of microglial cells resulting in the observed reduction of chemokines on protein level
Summary
Treatment of bacterial meningitis (BM) with sulfonamids was successfully introduced in the 1930’s and the advent of third generation cephalosporins further reduced the mortality rates [1]. Histopathological assessments in experimental models as well as autopsy cases showed three forms of injury in the central nervous system: apoptosis occurs in the hippocampal dentate gyrus, necrosis is found in the cerebral cortex, and loss of type 1 neurons in the spiral ganglion. These forms of neuronal damage cause neurological sequelae such as learning deficits, seizure disorders and hearing impairments respectively [8,9,10]
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