Neuroinflammatory Role of Prostaglandins during Experimental Meningitis: Evidence Suggestive of an in Vivo Relationship between Nitric Oxide and Prostaglandins

Boje, Kathleen M. K.; Jaworowicz, David; Raybon, Joseph

doi:10.1124/jpet.102.041533

Cited by 36 publications

(26 citation statements)

References 40 publications

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“…53). NOS2 induction, and the subsequent generation of NO, in particular, were argued to contribute to pathology in S. pneumoniae BM (55,87). We found that induction of mRNA for NOS2, but not COX2, was strongly diminished in infected IFN-g gene-deficient animals at both 48 and 72 h p.i.…”

Section: Discussionmentioning

confidence: 58%

Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

Mitchell

Yau

McQuillan

et al. 2012

The Journal of Immunology

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The pathology associated with Streptococcus pneumoniae meningitis results largely from activation of immune-associated pathways. We systematically investigated the production of IFN subtypes, as well as their influence on pathology, in a mouse model of S. pneumoniae meningitis. Despite the occurrence of a mixed IFN type I/II gene signature, no evidence for production or involvement of type I IFNs in disease progression was found. In contrast, type II IFN (IFN-γ) was strongly induced, and IFN-γ−/− mice were significantly protected from severe disease. Using intracellular cytokine staining and targeted cell-depletion approaches, NK cells were found to be the dominant source of IFN-γ. Furthermore, production of IFN-γ was found to be dependent upon ASC and IL-18, indicating that an ASC-dependent inflammasome pathway was responsible for mediating IFN-γ induction. The influence of IFN-γ gene deletion on a range of processes known to be involved in bacterial meningitis pathogenesis was examined. Although neutrophil numbers in the brain were similar in infected wild-type and IFN-γ−/− mice, both monocyte recruitment and CCL2 production were less in infected IFN-γ−/− mice compared with infected wild-type controls. Additionally, gene expression of NO synthase was strongly diminished in infected IFN-γ−/− mice compared with infected controls. Finally, bacterial clearance was enhanced in IFN-γ−/− mice, although the underlying mechanism remains unclear. Together, these data suggest that inflammasome-dependent IFN-γ contributes via multiple pathways to pathology during S. pneumoniae meningitis.

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Section: Discussionmentioning

confidence: 58%

Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

Mitchell

Yau

McQuillan

et al. 2012

The Journal of Immunology

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“…In brain as in other organs, COX-2 is markedly upregulated in pathologies associated with inflammation and contributes to cytotoxicity both in vitro and in vivo 30,47,48 (see Hurley and colleagues 13 for a review). Although in the neurotoxicity associated with activation of NMDA receptors COX-2-derived prostanoids rather then radicals play a major role, it is unknown whether this is also the case in inflammation.…”

Section: Fig 1 Time Course Of Cox-2 Mrna Expression After Neocorticamentioning

confidence: 97%

Prostanoids, not reactive oxygen species, mediate COX‐2–dependent neurotoxicity

Manabe

Anrather

Kawano

et al. 2004

Annals of Neurology

129

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The prostaglandin synthesizing enzyme cyclooxygenase-2 (COX-2) has emerged as a critical pathogenic factor in brain diseases associated with activation of N-methyl-D-aspartate (NMDA) receptors, including stroke and neurodegenerative diseases. However, the COX-2 reaction products responsible for these deleterious effects have not been identified. In particular, the relative contribution to the neurotoxicity of COX-2-derived prostanoids and reactive oxygen species has not been defined. We found that the brain damage produced by direct injection of NMDA into the somatosensory cortex is attenuated by the COX-2 inhibitor NS-398 or in COX-2-null mice, but that the associated production of free radicals is not. Furthermore, COX-2 inhibition reduces the lesions even if the deleterious effects of free radicals are eliminated by the scavenger superoxide dismutase. The protection exerted by NS-398 is counteracted by a stable analog of prostaglandin E2. The findings directly implicate COX-2-derived prostanoids, rather then radicals, in the COX-2-dependent component of the damage mediated by NMDA receptors and strengthen the rationale for using COX-2 inhibitors in the treatment of neurological diseases associated with glutamate neurotoxicity.

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“…Amongst the three isoforms of NOS, iNOS shows the highest activity. In fact, overproduction of NO by iNOS is implicated in a number of pathogenic conditions [27] including CDDP-induced degeneration of the SV [28]. Thus, we have examined expression of iNOS in the SV following CDDP treatment.…”

Section: Reactive Radical Species In Damage Of Marginal Cellsmentioning

confidence: 99%

Mechanisms of Apoptosis Induced by Cisplatin in Marginal Cells in Mouse Stria Vascularis

Lee

Nakagawa²,

Kita

et al. 2004

ORL

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Degeneration of the stria vascularis (SV) is amongst the major causes of cisplatin (CDDP)-induced hearing impairment. The pathways of apoptosis occurring in the SV due to CDDP were examined using a mouse experimental model. Temporal bones of adult C57BL/6 mice were collected on days 3, 7 and 14 after the local application of CDDP. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and immunostaining for apoptosis-related proteins or reactive radical species were employed for analysis. Local application of CDDP caused apoptotic cell death of marginal cells 3 days after CDDP treatment. Immunohistochemical analyses demonstrated activation of caspase-3 and -9, but not -8, and redistribution of cytochrome c in affected marginal cells, indicating a caspase-dependent, mitochondrion-mediated apoptotic pathway in marginal cells. Temporary expression of hydroxynonenal, nitrotyrosine and inducible nitric oxide synthase in the SV was observed at the induction of apoptosis in marginal cells. CDDP toxicity generates reactive radical species in the SV, which causes mitochondrial membrane permeabilization leading to apoptosis of marginal cells.

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Neuroinflammatory Role of Prostaglandins during Experimental Meningitis: Evidence Suggestive of an in Vivo Relationship between Nitric Oxide and Prostaglandins

Cited by 36 publications

References 40 publications

Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

Prostanoids, not reactive oxygen species, mediate COX‐2–dependent neurotoxicity

Mechanisms of Apoptosis Induced by Cisplatin in Marginal Cells in Mouse Stria Vascularis

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