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Background: Gamma-aminobutyric acid (GABA) is found throughout the body. The regulation of GABA receptor (GABAR) reduces oxidative stress (OS). Ischemia/reperfusion injury after orthotopic liver transplantation (OLT) causes OS-induced graft damage. The effects of GABAR regulation in donors in vivo were investigated., Material and Methods: Donor rats received saline, a GABAR agonist or GABAR antagonist 4 h before surgery. Recipient rats were divided into four groups according to the donor treatments: laparotomy, OLT with saline, OLT with GABAR agonist and OLT with GABAR antagonist. Histopathological, biochemical and immunohistological examinations were performed at 6, 12 and 24 h after OLT. Protein assays were performed at 6 h after OLT. The 4-hydroxynonenal (4-HNE), ataxia-telangiectasia mutated kinase (ATM), phosphorylated histone H2AX (gammaH2AX), phosphatidylinositol-3 kinase (PI3K), Akt and superoxide dismutase (SOD) were assessed by western blot analysis., Results: In the univariate analysis, histopathological and biochemical profiles verified that the GABAR agonist reduced graft damage. Immunohistology revealed that the GABAR agonist prevented the induction of apoptosis. Measurement of 4-4-HNE levels confirmed OS-induced damage after OLT, and the GABAR agonist improved this damage. In the gammaH2AX, PI3K, Akt and antioxidant enzymes (SODs), ATM and H2AX were greatly increased after OLT, and were reduced by the GABAR agonist. In the multivariate analyses between multiple groups, histopathological assessment, aspartate aminotransferase level, immunohistological examinations for apoptotic induction and gammaH2AX showed statistical differences., Conclusions: A specific agonist demonstrated regulation of GABAR in vivo in the liver. This activation in vivo reduced OS after OLT via the ATM/H2AX pathway.

Background: γ-Aminobutyric acid exists throughout the body, and the brain γ-aminobutyric acid receptor (GABAR) regulation reduces oxidative stress (OS). Effects of GABAR regulation in the liver are unknown. Ischemia or reperfusion injury after orthotopic liver transplantation (OLT) or shear stress after split OLT (SOLT) with a small-for-size graft causes OS-induced graft damage. Here, the strategic potential of graft pretreatment in vivo and ex vivo by GABAR regulation was investigated., Materials and Methods: Recipient rats were divided into seven groups according to the graft pretreatments and graft types: (1) laparotomy, (2) OLT, (3) GABAR regulation in vivo and OLT, (4) GABAR regulation ex vivo and OLT, (5) SOLT, (6) GABAR regulation in vivo and SOLT, and (7) GABAR regulation ex vivo and SOLT. Survival study, biochemical assays, histopathologic or immunohistologic assessments, and Western blotting were performed at 6 h after OLT or SOLT., Results: Graft pretreatment in vivo prolonged survival after SOLT. Histopathologic and biochemical profiles verified that graft pretreatment in vivo reduced graft damage after OLT or SOLT. Immunohistologically, graft pretreatment in vivo prevented apoptotic inductions after OLT or SOLT. The 4-hydroxynonenal confirmed the OS after OLT or SOLT, and graft pretreatment in vivo improved the OS. Graft pretreatment in vivo decreased ataxia-telangiectasia-mutated kinase and H2AX after OLT or SOLT. Graft pretreatment in vivo increased phosphatidylinositol 3 kinase and Akt after SOLT. In contrast, GABAR regulation ex vivo did not work., Conclusions: Graft pretreatment in vivo, not ex vivo, prevented the ischemia or reperfusion injury-mediated OS after OLT or SOLT via the ataxia-telangiectasia-mutated kinase/H2AX pathway and the shear stress-mediated OS after SOLT with small-for-size graft via the phosphatidylinositol 3 kinase/Akt pathway., (Copyright © 2013 Elsevier Inc. All rights reserved.)