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Inflammatory Mediator Stimulation of Astrocytes and Meningeal Fibroblasts Induces Neuronal Degeneration via the Nitridergic Pathway
Author(s) -
Skaper Stephen D.,
Facci Laura,
Leon Alberta
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.64010266.x
Subject(s) - neurotoxicity , astrocyte , superoxide , nitric oxide synthase , tumor necrosis factor alpha , chemistry , superoxide dismutase , stimulation , nitric oxide , excitotoxicity , biology , pharmacology , nmda receptor , microbiology and biotechnology , biochemistry , oxidative stress , immunology , endocrinology , central nervous system , receptor , toxicity , organic chemistry , enzyme
The role of inflammatory cytokines in the pathogenesis of neurological disorders is not entirely clear. The neurotoxic effects of cytokines, and perhaps indirectly bacterial endotoxins, could be mediated by the stimulation of immunocompetent cells in the brain to produce toxic concentrations of nitric oxide (NO) and reactive nitrogen oxides. NO is a short‐lived, diffusible molecule that has a variety of biological activities including vasorelaxation, neurotransmission, and cytotoxicity. Both constitutive and inducible NO synthase has been described in astrocytes in vitro. Here we demonstrate that newborn mouse cortical astrocytes, when coincubated with neonatal mouse cerebellar granule cells or hippocampal neurons, induced neurotoxicity upon stimulation with endotoxin (lipopolysaccharide) (ED 50 30 ng/ml). Astrocytes were unresponsive to the cytokines tumor necrosis factor‐α or interleukin‐1β individually, but exhibited a marked synergistic stimulation in their combined presence. Moreover, meningeal fibroblasts treated with tumor necrosis factor‐α, but not interleukin‐1β or lipopolysaccharide, elaborated neurotoxicity for cocultured granule cells (ED 50 30 U/ml). In cocultures of immunostimulated astrocytes or meningeal fibroblasts, neurotoxicity was blocked by the NO synthase inhibitors N ω ‐nitro‐ l ‐arginine and N ω ‐nitro‐ d ‐arginine methyl ester, and by oxyhemoglobin, which inactivates NO. Astroglial‐induced neurotoxicity was not affected by N ‐methyl‐ d ‐aspartate receptor antagonists. Superoxide dismutase, which degrades superoxide anion, attenuated astrocyte‐ and fibroblast‐mediated neurotoxicity, indicating that endogenous superoxide anion may react with NO to form toxic peroxynitrite and its breakdown products. These findings suggest a potentially important role for glial‐ and meningeal fibroblast‐induced NO synthase in the pathophysiology of CNS disease states of immune or inflammatory origin.