Effect of specific activation of γ-aminobutyric acid receptor in vivo on oxidative stress-induced damage after extended hepatectomy

Lindsay B. Gardner, Tomohide Hori, Feng Chen, Ann Marie T. Baine, Toshiyuki Hata, Shinji Uemoto, Justin H. Nguyen

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Aim: γ-Aminobutyric acid (GABA) is a multifunctional molecule with various physiological effects throughout the body. The regulation of GABA receptor (GABAR) plays a key role in reducing the damage mediated by oxidative stress (OS). Extended hepatectomy causes fatal OS-induced injury in the liver remnant. We aimed to investigate the effect of a GABAR agonist in extended hepatectomy. Methods: Saline or a GABAR agonist (43.56nmol/g bodyweight of muscimol) was administrated intravenously at 4h preoperatively. C57BL/6 mice were divided into three groups: laparotomy only, 90% hepatectomy with saline and 90% hepatectomy with a GABAR agonist. Liver samples were obtained at 6h after surgery. Results: Survival curves were prolonged by the GABAR agonist. Histopathological findings and biochemical profiles showed that the GABAR agonist reduced liver damage. Immunohistological assessment demonstrated that the GABAR agonist prevented apoptotic induction. As shown by 4-hydroxynonenal, which reflects OS-induced damage, 90% hepatectomy caused OS and the GABAR agonist reduced OS. We measured ataxia-telangiectasia mutated kinase (ATM), H2AX, Akt and free radical scavenging enzymes because they may be affected by GABAR regulation, and found that Akt was greatly decreased after 90% hepatectomy, but it recovered with the GABAR agonist. Conclusion: GABAR is activated by a specific agonist in the liver in vivo. This activation reduces OS-mediated damage after extended hepatectomy in vivo, and the mechanism via an Akt-dependent pathway may be a key.

Original languageEnglish (US)
Pages (from-to)1131-1140
Number of pages10
JournalHepatology Research
Volume42
Issue number11
DOIs
StatePublished - Nov 2012

Keywords

  • Akt
  • Free radicals
  • Liver
  • Oxidative stress
  • γ-aminobutyric acid receptor

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases

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