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 (Pam3-Cys) (TLR2) and single-stranded unmethylated CpG-DNA (CpG) (TLR9)] alone and in combination with amyloid beta peptide (Abeta) 1-40. Abeta 1-40 stimulated microglial cells and macrophages primed by interferon-c in a dose-dependent manner. Co-administration of Abeta1-40 with LPS or Pam3-Cys led to an additive release of nitric oxide (NO) and tumour necrosis factor alpha (TNF-a). 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-a release compared with stimulation with CpG alone. Abeta 1-40 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 Abeta on innate immunity.
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 ¼ 12) on the release of proinflammatory bacterial components, the formation of neurotoxic compounds and neuronal injury compared with the standard therapy with ceftriaxone (n ¼ 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 ¼ 0.004) into the CSF and the CSF leucocyte count (p ¼ 0.011). This led to lower extracellular concentrations of hydroxyl radicals (p ¼ 0.034) and glutamate (p ¼ 0.016) in the hippocampal formation and a subsequent reduction of extracellular glycerol levels (p ¼ 0.018) and neuronal apoptosis in the dentate gyrus (p ¼ 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 b-lactam antibiotics in meningitis. Keywords: ceftriaxone, clindamycin, microdialysis, neuroprotection, Streptococcus pneumoniae meningitis. In the last four decades, mortality from community-acquired bacterial meningitis has remained unchanged (5-10% in children and 25% in adults) (Roos et al. 1997). Long-term neurological sequelae and death in bacterial meningitis are caused jointly by several factors: (i) the systemic inflammatory response of the host, leading to leucocyte extravasation into the subarachnoid space, vasculitis, brain oedema and secondary ischaemia; (ii) stimulation of resident microglia within the CNS by bacterial compounds and (iii) direct toxicity of bacterial haemolysins on neurones (Braun et al. 2002;Nau and Brück 2002;Stringaris et al. 2002). Of the various adjunctive therapeutic approaches effective in animals, only dexamethasone therapy has been shown to decrease hearing loss, overall neurologic sequelae and mortality in children with Haemophilus influenzae type B meningitis and adults with Streptoccocus pneumoniae Address correspondence and reprint requests to Dr Roland Nau, Georg-August University, Department of Neurology, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany. E-mail: rnau@gwdg.de This work is dedicated to Professor Dr. W. Creutzfeldt, former Director of the Dept. of Gastroenterology & Endocrinology, Georg-AugustUniversity, Göttingen, Germany, on occasion of his 80th birthday.
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.
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