Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation.
When activated by proinflammatory stimuli, microglia release substantial levels of glutamate, and mounting evidence suggests this contributes to neuronal damage during neuroinflammation. Prior studies indicated a role for the Xc exchange system, an amino acid transporter that antiports glutamate for cystine. Because cystine is used for synthesis of glutathione (GSH) synthesis, we hypothesized that glutamate release is an indirect consequence of GSH depletion by the respiratory burst, which produces superoxide from NADPH oxidase. Microglial glutamate release triggered by lipopolysaccharide was blocked by diphenylene iodonium chloride and apocynin, inhibitors of NADPH oxidase. This glutamate release was also blocked by vitamin E and elicited by lipid peroxidation products 4-hydroxynonenal and acrolein, suggesting that lipid peroxidation makes crucial demands on GSH. Although NADPH oxidase inhibitors also suppressed nitrite accumulation, vitamin E did not; moreover, glutamate release was largely unaffected by nitric oxide donors, inhibitors of nitric oxide synthase, or changes in gene expression. These findings indicate that a considerable degree of the neurodegenerative consequences of neuroinflammation may result from conversion of oxidative stress to excitotoxic stress. This phenomenon entails a biochemical chain of events initiated by a programmed oxidative stress and resultant mass-action amino acid transport. Indeed, some of the neuroprotective effects of antioxidants may be due to interference with these events rather than direct protection against neuronal oxidation.
Barger
Steven W
SW
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. bargerstevenw@uams.edu
Goodwin
Mary E
ME
Porter
Mandy M
MM
Beggs
Marjorie L
ML
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000378:metabolism*; D008954:Models, Biological; D009861:Onium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D014810:Vitamin E / Q000494:pharmacology
D000098:Acetophenones; D000975:Antioxidants; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009861:Onium Compounds; D014810:Vitamin E; D018698:Glutamic Acid; C007517:diphenyleneiodonium; C056165:acetovanillone