Glutamine-induced free radical production in cultured astrocytes

Arumugam R. Jayakumar, K. V Rama Rao, Arne Schousboe, Michael D Norenberg

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Ammonia is a neurotoxin implicated in the pathogenesis of hepatic encephalopathy, Reye's syndrome, inborn errors of the urea cycle, glutaric aciduria, and other metabolic encephalopathies. Brain ammonia is predominantly metabolized to glutamine in astrocytes by glutamine synthetase. 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 2-3 min (95%; P < 0.05), as well as at 1 and 3 h (42% and 49%, respectively; P < 0.05). Similarly treated cultured neurons failed to generate free radicals. Free radical production by glutamine was blocked by the antioxidants deferoxamine (40 μM) and α-phenyl-N-tert-butyl-nitrone (250 μM), as well as by the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (500 μM). Free radical production was also blocked by 6-diazo-5-oxo-L-norleucine (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-induced oxidative and/or nitrosative stress may represent a key mechanism in ammonia neurotoxicity.

Original languageEnglish
Pages (from-to)296-301
Number of pages6
JournalGLIA
Volume46
Issue number3
DOIs
StatePublished - May 1 2004

Fingerprint

Glutamine
Astrocytes
Free Radicals
Ammonia
Diazooxonorleucine
Metabolic Brain Diseases
Reye Syndrome
Glutaminase
Neurons
Glutamate-Ammonia Ligase
Deferoxamine
Hepatic Encephalopathy
Neurotoxins
Nitric Oxide Synthase
Cyclosporine
Urea
Permeability
Hydrolysis
Antioxidants
Brain

Keywords

  • Ammonia
  • Glutaminase
  • Mitochondrial permeability transition
  • Neurons
  • Oxidative stress

ASJC Scopus subject areas

  • Immunology

Cite this

Glutamine-induced free radical production in cultured astrocytes. / Jayakumar, Arumugam R.; Rao, K. V Rama; Schousboe, Arne; Norenberg, Michael D.

In: GLIA, Vol. 46, No. 3, 01.05.2004, p. 296-301.

Research output: Contribution to journalArticle

Jayakumar, AR, Rao, KVR, Schousboe, A & Norenberg, MD 2004, 'Glutamine-induced free radical production in cultured astrocytes', GLIA, vol. 46, no. 3, pp. 296-301. https://doi.org/10.1002/glia.20003
Jayakumar, Arumugam R. ; Rao, K. V Rama ; Schousboe, Arne ; Norenberg, Michael D. / Glutamine-induced free radical production in cultured astrocytes. In: GLIA. 2004 ; Vol. 46, No. 3. pp. 296-301.
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