Toxicity in Neuronal Cells Caused by Cerebrospinal Fluid from Pneumococcaland Gram-Negative Meningitis

Täuber, Martin G.; Sachdeva, Meena; Kennedy, Stephen L.; Loetscher, Hansruedi; Lesslauer, Werner

doi:10.1093/infdis/166.5.1045

Cited by 32 publications

(16 citation statements)

References 30 publications

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“…HN33 is an immortalized cell line derived from somatic cell fusion of mouse hippocampal neurons and N18TG2 neuroblastoma cells (13). HN33 cells express a broad range of neuronal signaling properties (13)(14)(15)(16)(17)(18) and have been used to investigate pathophysiological features of neuronal injury states, including meningitis (19), polyglutamine disease (20), oxidative stress (21), and ischemia (22). HN33 cells were cultured as described by Shi et al (22), with modifications.…”

Section: Methodsmentioning

confidence: 99%

Vascular endothelial growth factor: Direct neuroprotective effect in in vitro ischemia

Jin

Mao

Greenberg

2000

Proc. Natl. Acad. Sci. U.S.A.

633

429

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Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic peptide with recently identified neurotrophic effects. Because some neurotrophic factors can protect neurons from hypoxic or ischemic injury, we investigated the possibility that VEGF has similar neuroprotective properties. In HN33, an immortalized hippocampal neuronal cell line, VEGF reduced cell death associated with an in vitro model of cerebral ischemia: at a maximally effective concentration of 50 ng͞ml, VEGF approximately doubled the number of cells surviving after 24 h of hypoxia and glucose deprivation. To investigate the mechanism of neuroprotection by VEGF, the expression of known target receptors for VEGF was measured by Western blotting, which showed that HN33 cells expressed VEGFR-2 receptors and neuropilin-1, but not VEGFR-1 receptors. The neuropilin-1 ligand placenta growth factor-2 failed to reproduce the protective effect of VEGF, pointing to VEGFR-2 as the site of VEGF's neuroprotective action. Two phosphatidylinositol 3-kinase inhibitors, wortmannin and LY294002, reversed the neuroprotective effect of VEGF, implicating the phosphatidylinositol 3-kinase͞Akt signal transduction system in VEGF-mediated neuroprotection. VEGF also protected primary cultures of rat cerebral cortical neurons from hypoxia and glucose deprivation. We conclude that in addition to its known role as an angiogenic factor, VEGF may exert a direct neuroprotective effect in hypoxic-ischemic injury.

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Section: Methodsmentioning

confidence: 99%

Vascular endothelial growth factor: Direct neuroprotective effect in in vitro ischemia

Jin

Mao

Greenberg

2000

Proc. Natl. Acad. Sci. U.S.A.

633

429

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“…Previous experiments had suggested that the mu-rine neuronal cell line HN 33.1 was sensitive to various cytokines, in particular TNF [29]. These studies indicated that the cytotoxicity in CSF from animals with bacterial meningitis was attributable to TNF since soluble TNF receptors blocked virtually all of this activity except that observed late after challenge with either live pneumococci or pneumococcal cell wall.…”

Section: Soluble Inflammatory Mediatorsmentioning

confidence: 96%

“…In some instances a net increase in bacterial titer was preceded by lag times as long as [20][21][22][23][24][25][26][27][28][29][30] hours after the intracerebral inoculation of an inoculum of 10 3-104 cfu. Once bacterial growth commences, the time of onset ofCSF leukocytosis is a remarkably sensitive indicator of the bacterial concentration.…”

Section: How Microorganisms Challenge the Host In Bacterial Meningitismentioning

confidence: 99%

Mechanisms of Brain Injury in Bacterial Meningitis: Workshop Summary

Pfister

Fontana²,

Täuber³

et al. 1994

Clinical Infectious Diseases

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Morbidity and mortality associated with bacterial meningitis remain high, although antibiotic therapy has improved during recent decades. The major intracranial complications of bacterial meningitis are cerebrovascular arterial and venous involvement, brain edema, and hydrocephalus with a subsequent increase of intracranial pressure. Experiments in animal models and cell culture systems have focused on the pathogenesis and pathophysiology of bacterial meningitis in an attempt to identify the bacterial and/or host factors responsible for brain injury during the course of infection. An international workshop entitled "Bacterial Meningitis: Mechanisms of Brain Injury" was organized by the Department of Neurology at the University of Munich and was held in Eibsee, Germany, in June 1993. This conference provided a forum for the exchange of current information on bacterial meningitis, including data on the clinical spectrum of complications, the associated morphological alterations, the role of soluble inflammatory mediators (in particular cytokines) and of leukocyte-endothelial cell interactions in tissue injury, and the molecular mechanisms of neuronal injury, with potential mediators such as reactive oxygen species, reactive nitrogen species, and excitatory amino acids. It is hoped that a better understanding of the pathophysiological events that take place during bacterial meningitis will lead to the development of new therapeutic regimens.Although the recent licensure of Haeniophilus influenzae type b (Hib) polysaccharide conjugate protein vaccines has had a marked impact on the incidence of invasive Hib disease in the United States and Western Europe. bacterial meningitis overall remains a significant problem worldwide. In addition, despite the introduction of new antimicrobial agents and improved diagnostic techniques, the mortality and morbidity associated with bacterial meningitis remain unacceptably high. This discrepancy between a rapid bacteriologic response at the site of infection (i.e .. eradication of viable bacteria from the CSF due to treatment with potent bactericidal agents) and the persistence of the associated neurological sequelae and mortality has prompted intense investigation over the past two decades into the pathophysiology of this disease. Indeed. recent clinical studies have employed adjunctive agents (e.g .. dexamethasone) in an attempt to reduce mortality and alleviate neurological sequelae [1][2][3][4]. These studies and the resulting recommendations regarding the use of adjunctive dexamethasone have recently been reviewed [5.6].In line with the current emphasis on the pathogenesis and pathophysiology of bacterial meningitis. two workshops were held in California in the 1980s [7]. Recognizing that many advances have been made in this field in the several years since those meetings. the Department of Neurology at the University of Munich organized a similar workshop, which was held in Eibsce. Germanv. on 25 and 26 June 1993. As IS evident from its title-"Bacterial Meningitis: Mechanisms...

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“…In fact, already in 1957 and 1962, it was shown that the CSF has toxic properties [33,34] . Meanwhile, several others reported that the CSF is neurotoxic, either derived from meningitis patients [35] or different coma patients [36] or from lupus erythematosus mice models [37] . More importantly, Sen et al [38] showed that CSF from ALS patients displayed neurotoxicity to motoneurons by elevating intracellular calcium, possibly via AMPA/kainate receptors.…”

Section: Bioassay Of Cholinergic Neuronsmentioning

confidence: 99%

Analysis of Cerebrospinal Fluid of Alzheimer Patients

et al. 2008

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Alzheimer’s disease (AD) is a severe, progressive and chronic disorder with strong cognitive deficits. Diagnosis of probable AD can be performed by measuring biomarkers in cerebrospinal fluid (CSF). The aim of the present study was to measure CSF levels of nerve growth factor (NGF), the anti-NGF auto-antibody, andthe cholinesterases AChE and BChE, and to correlate them with β-amyloid, tau and phospho-tau-181. We could show that NGF-like immunoreactivity, but not anti-NGF auto-antibody, was significantly enhanced in AD patients compared to healthy subjects, while both cholinesterases were not changed. β-Amyloid(1–42) was decreased, while tau and phospho-tau-181 were increased. The commercial Promega NGF ELISA detected mature NGF but not wild-type-human-pro-NGF. Using a bioassay of brain slices, we showed that recombinant mature NGF enhanced survival of cholinergic neurons, while wild-type human pro-NGF displayed a less pronounced effect. The addition of CSF to brain slices exhibited strong toxic effects on the survival of cholinergic neurons. We conclude that in CSF of AD patients (at least partly) mature NGF-like immunoreactivity is enhanced, and is masked in a bioassay by the toxic properties of CSF.

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Toxicity in Neuronal Cells Caused by Cerebrospinal Fluid from Pneumococcaland Gram-Negative Meningitis

Cited by 32 publications

References 30 publications

Vascular endothelial growth factor: Direct neuroprotective effect in in vitro ischemia

Vascular endothelial growth factor: Direct neuroprotective effect in in vitro ischemia

Mechanisms of Brain Injury in Bacterial Meningitis: Workshop Summary

Analysis of Cerebrospinal Fluid of Alzheimer Patients

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