Calcium in the mechanism of ammonia-induced astrocyte swelling

Arumugam R. Jayakumar, Kakulavarapu V. Rama Rao, Xiaoying Y. Tong, Michael D Norenberg

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Brain edema, due largely to astrocyte swelling, is an important clinical problem in patients with acute liver failure. While mechanisms underlying astrocyte swelling in this condition are not fully understood, ammonia and associated oxidative/nitrosative stress appear to be involved. Mechanisms responsible for the increase in reactive oxygen/nitrogen species (RONS) and their role in ammonia-induced astrocyte swelling, however, are poorly understood. Recent studies have demonstrated a transient increase in intracellular Ca2+ in cultured astrocytes exposed to ammonia. As Ca2+ is a known inducer of RONS, we investigated potential mechanisms by which Ca2+ may be responsible for the production of RONS and cell swelling in cultured astrocytes after treatment with ammonia. Exposure of cultured astrocytes to ammonia (5 mM) increased the formation of free radicals, including nitric oxide, and such increase was significantly diminished by treatment with the Ca2+ chelator 1,2-bis-(o-aminophenoxy)-ethane-N,N, -N′,N′-tetraacetic acid tetraacetoxy-methyl ester (BAPTA). We then examined the activity of Ca2+-dependent enzymes that are known to generate RONS and found that ammonia significantly increased the activities of NADPH oxidase (NOX), constitutive nitric oxide synthase (cNOS), and phospholipase A2 (PLA2) and such increases in activity were significantly diminished by BAPTA. Pre-treatment of cultures with 7-nitroindazole, apocyanin, and quinacrine, respective inhibitors of cNOS, NOX, and PLA2, all significantly diminished RONS production. Additionally, treatment of cultures with BAPTA or with inhibitors of cNOS, NOX, and PLA2 reduced ammonia-induced astrocyte swelling. These studies suggest that the ammonia-induced rise in intracellular Ca2+ activates free radical producing enzymes that ultimately contribute to the mechanism of astrocyte swelling.

Original languageEnglish
Pages (from-to)252-257
Number of pages6
JournalJournal of Neurochemistry
Volume109
Issue numberSUPPL. 1
DOIs
StatePublished - May 1 2009

Fingerprint

Ammonia
Astrocytes
Swelling
Reactive Nitrogen Species
Calcium
Reactive Oxygen Species
Nitrogen
Oxygen
NADPH Oxidase
Phospholipases A2
Nitric Oxide Synthase
Free Radicals
Quinacrine
Ethane
Oxidative stress
Acute Liver Failure
Brain Edema
Enzymes
Therapeutics
Chelating Agents

Keywords

  • Brain edema
  • Hepatic encephalopathy
  • NADPH oxidase
  • Nitric oxide synthase
  • Oxidative/nitrosative stress
  • Phospholipase A2

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Calcium in the mechanism of ammonia-induced astrocyte swelling. / Jayakumar, Arumugam R.; Rama Rao, Kakulavarapu V.; Tong, Xiaoying Y.; Norenberg, Michael D.

In: Journal of Neurochemistry, Vol. 109, No. SUPPL. 1, 01.05.2009, p. 252-257.

Research output: Contribution to journalArticle

Jayakumar, Arumugam R. ; Rama Rao, Kakulavarapu V. ; Tong, Xiaoying Y. ; Norenberg, Michael D. / Calcium in the mechanism of ammonia-induced astrocyte swelling. In: Journal of Neurochemistry. 2009 ; Vol. 109, No. SUPPL. 1. pp. 252-257.
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