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The Journal of Neuroscience, May 3, 2006, 26(18):4774-4784; doi:10.1523/JNEUROSCI.0120-06.2006

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Neurobiology of Disease
Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes

A. R. Jayakumar,¹ K. S. Panickar,¹ Ch. R. K. Murthy, ⁴ and M. D. Norenberg^1,2,3

Departments of ¹Pathology and ²Biochemistry and Molecular Biology, University of Miami School of Medicine, ³Veterans Affairs Medical Center, Miami, Florida 33101, and ⁴Department of Animal Sciences, University of Hyderabad, India, 500 046

Correspondence should be addressed to Dr. Michael D. Norenberg, Department of Pathology (D-33), University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101. Email: mnorenbe{at}med.miami.edu

Hepatic encephalopathy (HE) is a major neurological complication in patients with severe liver failure. Elevated levels of ammonia have been strongly implicated as a factor in HE, and astrocytes appear to be the primary target of its neurotoxicity. Mechanisms mediating key aspects of ammonia-induced astrocyte dysfunction such as cell swelling and inhibition of glutamate uptake are not clear. We demonstrated previously that cultured astrocytes exposed to ammonia increase free radical production. We now show that treatment with antioxidants significantly prevents ammonia-induced astrocyte swelling as well as glutamate uptake inhibition. Because one consequence of oxidative stress is the phosphorylation of mitogen-activated protein kinases (MAPKs), we investigated whether phosphorylation of MAPKs may mediate astrocyte dysfunction. Primary cultured astrocytes exposed to 5 mM NH₄Cl for different time periods (1–72 h) significantly increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38^MAPK, and c-Jun N-terminal kinase (JNK) 1/2/3, which was inhibited by appropriate MAPK inhibitors 1, 4-diamino-2, 3-dicyano-1, 4-bis (2-aminophenylthio) butadiene (UO126; for ERK1/2), trans-1-(4-hydroxyclyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole (SB 239063; for p38^MAPK), and anthra[1,9-cd]pyrazol-6(2H)-one (SP600125; for JNK1/2/3), as well as by antioxidants. Kinase inhibitors partially or completely prevented astrocyte swelling. Although SB239063 and SP600125 significantly reversed glutamate uptake inhibition and ammonia-induced decline in glutamate-aspartate transporter protein levels, UO126 did not, indicating a differential effect of these kinases in ammonia-induced astrocyte swelling and glutamate transport impairment. These studies strongly suggest the involvement of oxidative stress and phosphorylation of MAPKs in the mechanism of ammonia-induced astrocyte dysfunction associated with ammonia neurotoxicity.

Key words: ammonia; astrocyte swelling; glutamate uptake; oxidative stress; MAP kinases; hepatic encephalopathy

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Received Oct. 5, 2005; revised Feb. 27, 2006; accepted March 2, 2006.

Correspondence should be addressed to Dr. Michael D. Norenberg, Department of Pathology (D-33), University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101. Email: mnorenbe{at}med.miami.edu

This article has been cited by other articles:

				A. R. Jayakumar, M. Liu, M. Moriyama, R. Ramakrishnan, B. Forbush III, P. V. B. Reddy, and M. D. Norenberg Na-K-Cl Cotransporter-1 in the Mechanism of Ammonia-induced Astrocyte Swelling J. Biol. Chem., December 5, 2008; 283(49): 33874 - 33882. [Abstract] [Full Text] [PDF]

				Y.-B. Ouyang, L. A. Voloboueva, L.-J. Xu, and R. G. Giffard Selective Dysfunction of Hippocampal CA1 Astrocytes Contributes to Delayed Neuronal Damage after Transient Forebrain Ischemia J. Neurosci., April 18, 2007; 27(16): 4253 - 4260. [Abstract] [Full Text] [PDF]

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