Pretreatment of Small-for-Size Grafts In Vivo by γ-Aminobutyric Acid Receptor Regulation against Oxidative Stress-Induced Injury in Rat Split Orthotopic Liver Transplantation
Background. Graft pretreatment to limit postoperative damage has the advantage of overcoming a current issue in liver transplantation (LT). The strategic potential of graft pretreatment in vivo by a specific agonist for γ-aminobutyric acid receptor (GABAR) was investigated in the rat LT model with a small-for-size graft (SFSG). Methods. Recipient rats were divided into three groups according to donor treatments and recipient surgeries: (i) saline and laparotomy, (ii) saline and split orthotopic liver transplantation (SOLT) with 40%-SFSG, and (iii) GABAR agonist and SOLT with 40%-SFSG. Survival was evaluated. Blood and liver samples were collected 6？h after surgery. Immunohistological assessment for apoptotic induction and western blotting for 4-hydroxynonenal, ataxia-telangiectasia mutated kinase (ATM), histone H2AX, phosphatidylinositol-3 kinase (PI3K), Akt, and free radical scavenging enzymes were performed. Results. Pretreatment by GABAR showed improvement in survival, histopathological assessment, and biochemical tests. Apoptotic induction and oxidative stress were observed after SOLT with an SFSG, and this damage was limited by GABAR regulation. GABAR regulation appeared to reduce DNA damage via the ATM/H2AX pathway and to promote cell survival via the PI3K/Akt pathway. Conclusions. Pretreatment in vivo by GABAR regulation improves graft damage after SOLT with an SFSG. This strategy may be advantageous in LT. 1. Introduction Oxygen is required for cell survival. However, oxygen also poses a potential hazard via reactive oxygen species (ROS) and reactive nitrogen species (RNS), with biological and functional alterations of lipids, proteins, and deoxyribonucleic acid (DNA) [1–3]. Therefore, ROS/RNS have been initially considered as harmful products of the normal aerobic metabolism. The control of ROS/RNS production plays physiological roles, especially, in regulating cell signaling to involve cell proliferation, differentiation, and apoptosis [1–3]. Oxidative stress (OS) mediated by free radicals is defined as an imbalance between the production of ROS/RNS and the antioxidant capacity of the cell [1–3]. These antioxidants ensure a defense against ROS/RNS-induced OS [2]. The predominant inhibitory neurotransmitter in the brain is γ-aminobutyric acid (GABA), and almost all researchers have focused on GABA or the regulation of GABA receptor (GABAR) in the brain [4–8]. Currently, GABA is considered to be a multifunctional molecule with various physiological effects throughout the body [9, 10]. In the brain, many researchers have found that the regulation
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