ABSTRACT
The interaction of endogenous and exogenous stimulators of innate immunity was examined in primary cultures of mouse microglial cells and macrophages after application of defined Toll-like receptor (TLR) agonists [lipopolysaccharide (LPS) (TLR4), the synthetic lipopeptide Pam3Cys-Ser-Lys4 (Pam3Cys) (TLR2) and single-stranded unmethylated CpG-DNA (CpG) (TLR9)] alone and in combination with amyloid beta peptide (Abeta) 1-40. Abeta1-40 stimulated microglial cells and macrophages primed by interferon-gamma in a dose-dependent manner. Co-administration of Abeta1-40 with LPS or Pam3Cys led to an additive release of nitric oxide (NO) and tumour necrosis factor alpha (TNF-alpha). This may be one reason for the clinical deterioration frequently observed in patients with Alzheimer's disease during infections. In contrast, co-application of Abeta1-40 with CpG led to a substantial decrease of NO and TNF-alpha release compared with stimulation with CpG alone. Abeta1-40 and CpG did not co-localize within the same subcellular compartment, making a direct physicochemical interaction as the cause of the observed antagonism very unlikely. This suggests that not all TLR agonists enhance the stimulatory effect of A beta on innate immunity.
Subject(s)
Amyloid beta-Peptides/pharmacology , DNA-Binding Proteins/antagonists & inhibitors , Inflammation/physiopathology , Lipopolysaccharides/pharmacology , Lipoproteins/pharmacology , Microglia/drug effects , Peptide Fragments/pharmacology , Receptors, Cell Surface/antagonists & inhibitors , Receptors, Immunologic/agonists , Amyloid beta-Peptides/metabolism , Analysis of Variance , Animals , Animals, Newborn , Blotting, Western/methods , Brain/cytology , Cell Survival/drug effects , Cells, Cultured , Cytokines/metabolism , DNA, Bacterial/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Enzyme-Linked Immunosorbent Assay/methods , Immunohistochemistry/methods , Inflammation/chemically induced , Lectins/metabolism , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Microglia/physiology , Microscopy, Confocal/methods , Nitrites/metabolism , Peptide Fragments/metabolism , Toll-Like Receptor 2 , Toll-Like Receptor 4 , Toll-Like Receptor 9ABSTRACT
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.
Subject(s)
Antioxidants/pharmacology , Melatonin/pharmacology , Meningitis, Pneumococcal/drug therapy , Animals , Antioxidants/metabolism , Cell Death/drug effects , Cell Line , Cells, Cultured , Hippocampus/cytology , Humans , Melatonin/cerebrospinal fluid , Meningitis, Pneumococcal/cerebrospinal fluid , Meningitis, Pneumococcal/pathology , Mice , Mice, Inbred C57BL , Neurons/drug effects , Oxidative Stress , Rabbits , Superoxide Dismutase/physiologyABSTRACT
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.
