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Query: UMLS:C0085437 (bacterial meningitis)
 4,038 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis of granular cells in the dentate gyrus frequently occurs in animal models of bacterial meningitis. In 37 autopsy cases of bacterial meningitis we evaluated, by light microscopy and in-situ tailing, whether this pattern of neuronal damage is of relevance in humans. Neuronal apoptoses in the dentate gyrus (density 1 to 19/mm2) were observed in 26 cases of bacterial meningitis and in none of 10 aged-matched control cases dying from non-neurological diseases. The density of apoptotic neurons depended on the interval between the onset of symptoms of meningitis and death (death within the first 2 days: 1.8+/-2.8 apoptoses/mm2; later than 18 days: 1.8+/-1.7/mm2; compared to death between days 3 and 18: 7.4+/-6.6 apoptoses/mm2, p = 0.007 and 0.004, respectively). Neuronal apoptosis in the dentate gyrus was not linked to neuronal damage in other parts of the brain or previous treatment with corticosteroids. Since learning deficits are frequently observed in survivors of bacterial meningitis, strategies to reduce the density of apoptotic neurons in the dentate gyrus may decrease the frequency of neurological sequela in patients surviving bacterial meningitis.
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PMID:Apoptosis of neurons in the dentate gyrus in humans suffering from bacterial meningitis. 1019 18

Neuronal apoptosis in the dentate gyrus has been observed in animal models of bacterial meningitis and in humans dying in the course of the disease. To evaluate the mechanisms of neuronal cell death, hippocampal sections of 20 patients dying from bacterial meningitis were investigated by immunohistochemistry using antibodies against the proform of caspase-3 and the active enzyme, bcl-2, bax and p53. In the dentate granule cell layer, the median density of neurons with an apoptotic morphology was 7.6/mm2 (0-15.6/mm2). The median density of immunoreactive neurons was 2.3/mm2 (procaspase-3), 0.9/mm2 (activated caspase-3), 1.8/mm2 (bcl-2), 1.1/mm2 (bax) and 0.4/mm2 (p53). 80% of neurons immunoreactive for active caspase-3 had an apoptotic morphology, whereas only 10% of all procaspase-3 stained neurons showed signs of apoptosis. Apoptotic cell death is present in humans dying in the course of bacterial meningitis in the dentate gyrus of the Formatio hippocampi. Neuronal expression of caspase-3, bcl-2 and bax suggests an involvement of these proteins in neuronal death.
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PMID:Expression of death-related proteins in dentate granule cells in human bacterial meningitis. 1155 87

In bacterial meningitis, long-term neurological sequelae and death are caused jointly by several factors: (1) the systemic inflammatory response of the host, leading to leukocyte extravasation into the subarachnoid space, vasculitis, brain edema and secondary ischemia; (2) stimulation of resident microglia within the CNS by bacterial compounds; and (3) possible direct toxicity of bacterial compounds on neurons. Neuronal injury is mediated by the release of reactive oxygen intermediates, proteases, cytokines and excitatory amino acids, and is executed by the activation of transcription factors, caspases and other proteases. In experimental meningitis, dexamethasone as an adjunct to antibiotic treatment leads to an aggravation of neuronal damage in the hippocampal formation, suggesting that corticosteroids might not be the ideal adjunctive therapy. Several approaches that interfere selectively with the mechanisms of neuronal injury are effective in animal models, including the use of nonbacteriolytic protein synthesis-inhibiting antibiotics, antioxidants and inhibitors of transcription factors, matrix metalloproteinases, and caspases.
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PMID:Neuronal injury in bacterial meningitis: mechanisms and implications for therapy. 1180 37

In spite of improved antimicrobial therapy, bacterial meningitis still results in brain damage leading to significant long-term neurological sequelae in a substantial number of survivors, as confirmed by several recent studies. Meningitis caused by Streptococcus pneumoniae is associated with a particularly severe outcome. Experimental studies over the past few years have increased our understanding of the molecular mechanisms underlying the events that ultimately lead to brain damage during meningitis. Necrotic damage to the cerebral cortex is at least partly mediated by ischemia and oxygen radicals and therefore offers a promising target for adjunctive therapeutic intervention. Neuronal apoptosis in the hippocampus may represent the major pathological process responsible for cognitive impairment and learning disabilities in survivors. However, the mechanisms involved in causing this damage remain largely unknown. Anti-inflammatory treatment with corticosteroids aggravates hippocampal damage, thus underlining the potential shortcomings of current adjuvant strategies. In contrast, the combined inhibition of matrix metalloproteinase and tumour necrosis factor-alpha converting enzyme protected both the cortex and hippocampus in experimental meningitis, and may represent a promising new approach to adjunctive therapy. It is the hope that a more refined molecular understanding of the pathogenesis of brain damage during bacterial meningitis will lead to new adjunctive therapies.
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PMID:Current concepts in the pathogenesis of meningitis caused by Streptococcus pneumoniae. 1201 59

Neuronal injury in bacterial meningitis is caused by the interplay of host inflammatory responses and direct bacterial toxicity. We investigated the mechanisms by which pneumolysin, a cytosolic pneumococcal protein, induces damage to neurons. The toxicity after exposure of human SH-SY5Y neuroblastoma cells and hippocampal organotypic cultures to pneumolysin was time- and dose-dependent. Pneumolysin led to a strong calcium influx apparently mediated by pores on the cell membrane formed by the toxin itself and not by voltage-gated calcium channels. Buffering of intracellular calcium with BAPTA-AM [1, 2-bis (o-aminophenoxy) ethane N, N, N', N'-tetraacetic acid tetra(acetomethoxyl) ester] improved survival of neuronal cells following challenge with pneumolysin. Western blotting revealed increased phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) as early as 30 min after challenge with pneumolysin. SB 203580, a potent and selective inhibitor of p38 MAPK, rescued human neuronal cells from pneumolysin-induced death. Inhibition of the mitochondrial permeability transition pore using bongkrekate and caspase inhibition also improved survival following challenge with the toxin. Modulation of cell death pathways activated by pneumolysin may influence the outcome of pneumococcal meningitis.
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PMID:Neurotoxicity of pneumolysin, a major pneumococcal virulence factor, involves calcium influx and depends on activation of p38 mitogen-activated protein kinase. 1258 46

In patients with acute bacterial meningitis, hearing loss can be transient but is often permanent. The mechanisms underlying meningitis-associated hearing loss are not fully understood. Therefore, we investigated the morphological correlates of hearing loss in a rat model of pneumococcal meningitis. Transcutaneous intracisternal injection of Streptococcus pneumoniae resulted in a dose-dependent hearing loss (determined by auditory brainstem response audiometry), which was partially reversible during the acute stage. Nevertheless, a severe permanent hearing loss persisted until 2 weeks after infection. Suppurative labyrinthitis was accompanied by blood-labyrinth barrier disruption (determined by cochlear Evans blue extravasation), which correlated closely with hearing loss during the acute stage but not after recovery. Two weeks after infection, spiral ganglion neuronal density was markedly decreased and correlated with the severity of permanent hearing loss. Neuronal loss can be explained by the new finding of meningitis-associated spiral ganglion neuronal necrosis rather than apoptosis (determined by morphology, TUNEL staining, and immunohistochemistry).
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PMID:Morphological correlates of acute and permanent hearing loss during experimental pneumococcal meningitis. 1274 66

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.
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PMID:Increased neurogenesis after experimental Streptococcus pneumoniae meningitis. 1289 28

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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PMID:Melatonin is neuroprotective in experimental Streptococcus pneumoniae meningitis. 1568 96

Inflammatory processes occur in the central nervous system (CNS) through mechanisms that differ from other inflammation, and with distinct cellular effects. Neuronal injury in bacterial meningitis is not a monocausal event, but is mediated by several factors. One is possible direct toxicity of bacterial compounds. Lipoteichoic acid (LTA) is a cell wall component unique to Gram-positive bacteria. In a previous report, LTA could interact with CD14 to induce NF-kappaB activation, which is involved in transcriptional regulation of adhesion molecules, enzymes and cytokines. Although there are many aspects to neuroinflammation, the pathways involving the cyclooxygenase (COX)-2 and subsequent generation of prostaglandin clearly play a role. LTA has been shown to stimulate inflammatory responses in a number of in vivo and in vitro experimental models. However, little was known about the molecular mechanisms of LTA implicated in inflammatory responses in neurons. In this study, we characterized the mechanisms underlying signaling transduction in rat cortical neuronal cells challenged by LTA. Here, we first showed that in rat cortical neuronal cells, LTA might activate protein tyrosine kinase (PTK), phosphatidylcholine-specific phospholipase C (PC-PLC), and phosphatidylinositol-specific phospholipase C (PI-PLC) to induce protein kinase Cepsilon activation, which in turn induces extracellular signal-regulated kinase (ERK) activation, finally inducing PGE(2) release and COX-2 synthesis.
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PMID:Lipoteichoic acid induces prostaglandin E(2) release and cyclooxygenase-2 synthesis in rat cortical neuronal cells: involvement of PKCepsilon and ERK activation. 1646 74

Group B Streptococcus (GBS) is a major cause of bacterial meningitis and neurological morbidity in newborn infants. The cellular and molecular mechanisms by which this common organism causes CNS injury are unknown. We show that both heat-inactivated whole GBS and a secreted proteinaceous factor from GBS (GBS-F) induce neuronal apoptosis via the activation of murine microglia through a TLR2-dependent and MyD88-dependent pathway in vitro. Microglia, astrocytes, and oligodendrocytes, but not neurons, express TLR2. GBS as well as GBS-F induce the synthesis of NO in microglia derived from wild-type but not TLR2(-/-) or MyD88(-/-) mice. Neuronal death in neuronal cultures complemented with wild-type microglia is NO-dependent. We show for the first time a TLR-mediated mechanism of neuronal injury induced by a clinically relevant bacterium. This study demonstrates a causal molecular relationship between infection with GBS, activation of the innate immune system in the CNS through TLR2, and neurodegeneration. We suggest that this process contributes substantially to the serious morbidity associated with neonatal GBS meningitis and may provide a potential therapeutic target.
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PMID:A mechanism for neurodegeneration induced by group B streptococci through activation of the TLR2/MyD88 pathway in microglia. 1678 56


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