Neuronal injury in bacterial meningitis is a consequence of the direct toxicity of bacterial components and inflammatory and oxidative mechanisms. Adjunctive therapy with melatonin was investigated in vitro and in experimental meningitis. Cellular damage was reduced by treatment with melatonin in organotypic hippocampal cultures (P<.001) and in human SH-SY5Y cells (P<.01). Rabbits were infected intracisternally with Streptococcus pneumoniae and received either melatonin (20 mg/kg body weight/24 h; n=12) or saline (n = 11) intravenously. Twelve hours later, all rabbits received ceftriaxone (10 mg/kg body weight/h). The density of apoptotic dentate granule cells was lower in melatonin-treated rabbits (81.8+/-52.9 vs. 227.5+/-127.9 cells/mm(2); P=.002). The activity of superoxide dismutase in the hippocampal formation was higher (P=.04), and nitrite concentrations in cerebrospinal fluid were lower, after treatment with melatonin (P=.003). Melatonin reduced neuronal injury in vitro and in experimental meningitis, and it may be suitable as adjunctive therapy in human meningitis.

In animal models of Streptococcus pneumoniae meningitis, rifampin is neuroprotective in comparison to ceftriaxone. So far it is not clear whether this can be generalized for other protein synthesis-inhibiting antimicrobial agents. We examined the effects of the bactericidal protein synthesis-inhibiting clindamycin (n = 12) on the release of proinflammatory bacterial components, the formation of neurotoxic compounds and neuronal injury compared with the standard therapy with ceftriaxone (n = 12) in a rabbit model of pneumococcal meningitis. Analysis of the CSF and histological evaluation were combined with microdialysis from the hippocampal formation and the neocortex. Compared with ceftriaxone, clindamycin reduced the release of lipoteichoic acids from the bacteria (p = 0.004) into the CSF and the CSF leucocyte count (p = 0.011). This led to lower extracellular concentrations of hydroxyl radicals (p = 0.034) and glutamate (p = 0.016) in the hippocampal formation and a subsequent reduction of extracellular glycerol levels (p = 0.018) and neuronal apoptosis in the dentate gyrus (p = 0.008). The present data document beneficial effects of clindamycin compared with ceftriaxone on various parameters linked with the pathophysiology of pneumococcal meningitis and development of neuronal injury. This study suggests neuroprotection to be a group effect of bactericidal protein synthesis-inhibiting antimicrobial agents compared with the standard therapy with beta-lactam antibiotics in meningitis.

Neuronal damage in the hippocampal formation is a common feature in animal models of bacterial meningitis and human disease. In mouse and rabbit models of Streptococcus pneumoniae meningitis, proliferation of neural progenitor cells quantified by bromodeoxyuridine (BrdU) incorporation was enhanced in the subgranular layer of the dentate gyrus. In mice, the density of BrdU-labeled cells was maximal on Day 2 after infection. Approximately 60% of the cells labeled by BrdU between Days 7 and 10 after infection that remained present 28 days later had migrated into deeper layers of the dentate gyrus and differentiated into neurons, as evidenced by immunohistochemical staining for TUC-4, MAP-2 and beta-tubulin. This suggests that endogenous repair mechanisms may limit consequences of neuronal destruction after meningitis.

Hippocampal slices of newborn rats were exposed to either heat-inactivated Streptococcus pneumoniae R6 (hiR6) equivalent to 10(6) and 10(8) CFU/ml, lipoteichoic acid (LTA) (0.3 microg/ml and 30 microg/ml), peptidoglycans (PG) (0.3, 30, 50 and 100 microg/ml), pneumococcal DNA (pDNA) (0.3 and 30 microg/ml) or medium only (control). Cell injury was examined by Nissl staining, Annexin V and NeuN immunohistochemistry, and quantified by propidium iodide (PI) uptake and by determining neuron-specific enolase (NSE) concentration in the culture medium. Necrotic and apoptotic cell damage occurred in all treatment groups. Overall damage (Nissl and PI staining) was most prominent after hiR6 (10(8) CFU/ml), followed by LTA (30 microg/ml), pDNA (30 microg/ml), and not detectable after PG (30 microg/ml) exposure. PG (100 microg/ml) induced severe damage. Apoptotic cells were most frequent after exposure to LTA and hiR6. Damage in the neuronal cell layers (NeuN, NSE) was most severe after treatment with hiR6 (10(8) CFU/ml), followed by PG (100 microg/ml), pDNA (30 microg/ml), and LTA (30 microg/ml).

Apoptosis and necrosis in brain account for neurological sequelae in survivors of bacterial meningitis. In meningitis, several mechanisms may trigger death pathways leading to activation of transcription factors regulating caspases mRNA synthesis. Therefore, we used a multiprobe RNA protection assay (RPA) to examine the expression of 9 caspase‐mRNA in the course of experimental Streptococcus pneumoniae meningitis in mouse brain. Caspase‐6, ‐7 and ‐11 mRNA were elevated 6 hours after infection. 12 hours after infection caspases‐1, ‐2, ‐8 and ‐12 mRNA rose. Caspase‐14 mRNA was elevated 18 h and caspase‐3 mRNA 24 h after infection. In situ hybridization detected caspases‐3, ‐8, ‐11 and ‐12 mRNA in neurons of the hippocampal formation and neocortex. Development of sepsis was paralleled by increased transcription of caspases mRNA in the spleen.