Brain edema in acute liver failure: Inhibition by L-histidine

Kakulavarapu V Rama Rao, Pichili V B Reddy, Xiaoying Tong, Michael D Norenberg

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Brain edema and the associated increase in intracranial pressure are potentially lethal complications of acute liver failure (ALF). Astrocyte swelling (cytotoxic edema) represents a significant component of the brain edema in ALF, and elevated blood and brain ammonia levels have been strongly implicated in its formation. We earlier showed in cultured astrocytes that oxidative stress (OS) and the mitochondrial permeability transition (mPT) play major roles in the mechanism of ammonia-induced astrocyte swelling. Glutamine, a byproduct of ammonia metabolism, has also been shown to induce OS, the mPT, and astrocyte swelling. Such effects of glutamine were suggested to be mediated by its hydrolysis in mitochondria, potentially yielding high levels of ammonia in this organelle and leading to OS and the mPT. L-histidine, an inhibitor of mitochondrial glutamine transport, was recently shown to mitigate OS, mPT, and cell swelling in cultured astrocytes treated with ammonia. The present study examined whether L-histidine similarly abolishes OS, the mPT, and brain edema in a rat model of ALF. Treatment of rats with thioacetamide caused a significant degree of brain edema, which was associated with induction of OS and the mPT. These changes were completely abolished by L-histidine, supporting a key role of mitochondrial glutamine transport and hydrolysis in the mechanism of the brain edema associated with ALF.

Original languageEnglish
Pages (from-to)1400-1408
Number of pages9
JournalAmerican Journal of Pathology
Volume176
Issue number3
DOIs
StatePublished - Mar 1 2010

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Acute Liver Failure
Brain Edema
Histidine
Permeability
Ammonia
Oxidative Stress
Astrocytes
Glutamine
Hydrolysis
Thioacetamide
Intracranial Hypertension
Organelles
Edema
Mitochondria
Brain

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Brain edema in acute liver failure : Inhibition by L-histidine. / Rao, Kakulavarapu V Rama; Reddy, Pichili V B; Tong, Xiaoying; Norenberg, Michael D.

In: American Journal of Pathology, Vol. 176, No. 3, 01.03.2010, p. 1400-1408.

Research output: Contribution to journalArticle

Rao, Kakulavarapu V Rama ; Reddy, Pichili V B ; Tong, Xiaoying ; Norenberg, Michael D. / Brain edema in acute liver failure : Inhibition by L-histidine. In: American Journal of Pathology. 2010 ; Vol. 176, No. 3. pp. 1400-1408.
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