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While the synthesis of glutamine has generally been viewed as the principal means of ammonia detoxification, this presumed beneficial effect has been questioned as growing evidence suggest that some of the deleterious effects of ammonia may be mediated by glutamine rather than ammonia per se. Since ammonia is known to induce the production of free radicals in cultured astrocytes, we investigated whether such production might be mediated by glutamine. Treatment of astrocytes with glutamine (4.5 mM) increased free radical production at 2\u20133 min (95%;<jats:italic>P<\/jats:italic>&lt; 0.05), as well as at 1 and 3 h (42% and 49%, respectively;<jats:italic>P<\/jats:italic>&lt; 0.05). Similarly treated cultured neurons failed to generate free radicals. Free radical production by glutamine was blocked by the antioxidants deferoxamine (40 \u03bcM) and \u03b1\u2010phenyl\u2010<jats:italic>N<\/jats:italic>\u2010tert\u2010butyl\u2010nitrone (250 \u03bcM), as well as by the nitric oxide synthase inhibitor N<jats:sup>\u03c9<\/jats:sup>\u2010nitro\u2010L\u2010arginine methyl ester (500 \u03bcM). Free radical production was also blocked by 6\u2010diazo\u20105\u2010oxo\u2010L\u2010norleucine (1 mM), an inhibitor of glutaminase, suggesting that ammonia released by glutamine hydrolysis may be responsible for the generation of free radicals. Additionally, the mitochondrial permeability transition inhibitor, cyclosporin A, blocked free radical production by glutamine. The results indicate that astrocytes, but not neurons, generate free radicals following glutamine exposure. Glutamine\u2010induced oxidative and\/or nitrosative stress may represent a key mechanism in ammonia neurotoxicity. \u00a9 2004 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/glia.20003","type":"journal-article","created":{"date-parts":[[2004,3,23]],"date-time":"2004-03-23T13:36:06Z","timestamp":1080048966000},"page":"296-301","source":"Crossref","is-referenced-by-count":95,"title":["Glutamine\u2010induced free radical production in cultured astrocytes"],"prefix":"10.1002","volume":"46","author":[{"given":"Arumugam R.","family":"Jayakumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.V.","family":"Rama Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne","family":"Schousboe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael 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