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Neurosci Lett. 2009 Sep 22;462(2):109-12. doi: 10.1016/j.neulet.2009.06.090. Epub 2009 Jul 2.

Prolonged exposure to ammonia increases extracellular glutamate in cultured rat astrocytes.

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  • 1Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.

Abstract

Abnormal alteration of brain function is a characteristic complication of hepatic encephalopathy in both acute and chronic liver failure. Previous studies suggest that the pathogenesis of hepatic encephalopathy involves chronic glial edema with subsequent alteration of glioneuronal communication, N-methyl-d-aspartate (NMDA) receptor activation, and oxidative/nitrosative stress. In the present study, we investigated extracellular glutamate levels in cultured astrocytes under prolonged exposure to ammonia. Using an enzyme-linked high-performance liquid chromatography assay to detect glutamate, prolonged (48 h) exposure of cultured astrocytes to ammonia resulted in a concentration- and time-dependent increase in extracellular glutamate. Similar increases were observed when ammonia-containing medium (pH 7.8) was adjusted to the pH of control medium (pH 7.4), indicating that the effect is not due to pH. Treatment of astrocytes with an antioxidant (l-ascorbic acid), an NADPH oxidase inhibitor (apocynin), a Ca2+ chelator (BAPTA-AM), an NMDA receptor antagonist (NK801), or a mitochondrial permeability transition inhibitor (cyclosporine A) suppressed the increase of extracellular glutamate in response to prolonged ammonia exposure. Prolonged exposure to ammonia increased extracellular glutamate through the NMDA receptor, increased intracellular Ca2+ levels, and upregulation of excitatory amino acids. The addition of ATP further increased extracellular glutamate levels in astrocytes subjected to prolonged ammonia treatment (5mM, 48 h) in a dose-dependent manner. These results indicate that the deregulation of glutamate release from astrocytes may contribute to the dysfunction of glutamatergic neurons in patients with acute liver failure (ALF).

PMID:
19576960
[PubMed - indexed for MEDLINE]
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