Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation

Abstract

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.

Anti-inflammatory actions of a taurine analogue, ethane β-sultam, in phagocytic cells, in vivo and in vitro

“…Depletion of reduced glutathione will occur, which will be remedied by the synthesis of more of this antioxidant by the influx of cystine via the Xc exchange system which releases glutamate [37]. In these present studies increases in glutamate release were 19 apparent in microglia, but not macrophages, after bacterial stimulation.…”

“…However when microglia are activated, by pro-inflammtory stimuli, substantial levels of glutamate are released [37]. This is due to the activation of NADPHoxidase which generate superoxide, leading to the formation of hydroxyl radical via Fenton chemistry, resulting in oxidative stress.…”

P2X7 receptor mediates activation of microglial cells in prostate of chemically irritated rats

“…Microglias and astrocytes are regarded as "immune cells" in the nervous system, and can secrete some pro-inflammatory cytokines such as IL-1β, TNF-α, NGF, NO, prostaglandin and bradykinin following activation, leading to the exaggeration and persistence of pain by acting on other glial cells and neurons (25,26). Therefore, microglial cells play important roles in the pathogenesis of pathological pain (27,28). In rats with sciatic inflammation, intrathecal injection of minocycline, an inhibitor of microglial cell activation, was found to inhibit the abnormal mechanical pain with low threshold (29).…”

Reducing Neuroinflammation in Psychiatric Disorders: Novel Target of Phosphodiesterase 4 (PDE4) and Developing of the PDE4 Inhibitors

“…hyperramiied or ameboid/phagocytic [22], and may synthesize proinflammatory molecules, superoxide radicals, glutamate [23][24], and nitric oxide (NO) and ultimately clear infections and repair tissues. Alternatively, M2 activation, which can be triggered by cytokines such as IL-4, IL-13, or IL-25 [25]; [22], has been associated with a release of antiinflammatory cytokines (e.g.…”