Glutamine as a mediator of ammonia neurotoxicity: A critical appraisal

Jan Albrecht, Magdalena Zielińska, Michael D Norenberg

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Ammonia is a major neurotoxin implicated in hepatic encephalopathy (HE). Here we discuss evidence that many aspects of ammonia toxicity in HE-affected brain are mediated by glutamine (Gln), synthesized in excess from ammonia and glutamate by glutamine synthetase (GS), an astrocytic enzyme. The degree to which Gln is increased in brains of patients with HE was found to positively correlate with the grade of HE. In animals with HE, a GS inhibitor, methionine sulfoximine (MSO), reversed a spectrum of manifestations of ammonia toxicity, including brain edema and increased intracranial pressure, even though MSO itself increased brain ammonia levels. MSO inhibited, while incubation with Gln reproduced the oxidative stress and cell swelling observed in ammonia-exposed cultured astrocytes. Recent studies have shown that astrocytes swell subsequent to Gln transport into mitochondria and its degradation back to ammonia, which then generates reactive oxygen species and the mitochondrial permeability transition. This sequence of events led to the formulation of the " Trojan Horse" hypothesis. Further verification of the role of Gln in the pathogenesis of HE will have to account for: (1) modification of the effects of Gln by interaction of astrocytes with other CNS cells; and (2) direct effects of Gln on these cells. Recent studies have demonstrated a " Trojan Horse" -like effect of Gln in microglia, as well as an interference by Gln with the activation of the NMDA/NO/cGMP pathway by ammonia as measured in whole brain, a process that likely also involves neurons.

Original languageEnglish
Pages (from-to)1303-1308
Number of pages6
JournalBiochemical Pharmacology
Volume80
Issue number9
DOIs
StatePublished - Nov 1 2010

Fingerprint

Glutamine
Ammonia
Hepatic Encephalopathy
Methionine Sulfoximine
Brain
Astrocytes
Glutamate-Ammonia Ligase
Toxicity
Mitochondria
Oxidative stress
Brain Edema
Neurotoxins
Intracranial Pressure
Microglia
N-Methylaspartate
Neurons
Swelling
Glutamic Acid
Permeability
Reactive Oxygen Species

Keywords

  • " Trojan Horse" hypothesis
  • Ammonia
  • Astrocytes
  • Glutamine
  • Hepatic encephalopathy
  • Microglia
  • Mitochondria
  • NO/cGMP pathway

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Glutamine as a mediator of ammonia neurotoxicity : A critical appraisal. / Albrecht, Jan; Zielińska, Magdalena; Norenberg, Michael D.

In: Biochemical Pharmacology, Vol. 80, No. 9, 01.11.2010, p. 1303-1308.

Research output: Contribution to journalArticle

Albrecht, Jan ; Zielińska, Magdalena ; Norenberg, Michael D. / Glutamine as a mediator of ammonia neurotoxicity : A critical appraisal. In: Biochemical Pharmacology. 2010 ; Vol. 80, No. 9. pp. 1303-1308.
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