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GABA, ?-Aminobutyric Acid, Protects Against Severe Liver Injury.

ABSTRACT: BACKGROUND:Acute liver failure (ALF) from severe acute liver injury is a critical condition associated with high mortality. The purpose of this study was to investigate the impact of preemptive administration of ?-aminobutyric acid (GABA) on hepatic injury and survival outcomes in mice with experimentally induced ALF. MATERIALS AND METHODS:To induce ALF, C57BL/6NHsd mice were administered GABA, saline, or nothing for 7 d, followed by intraperitoneal administration of 500 ?g of tumor necrosis factor ? and 20 mg of D-galactosamine. The study mice were humanely euthanized 4-5 h after ALF was induced or observed for survival. Proteins present in the blood samples and liver tissue from the euthanized mice were analyzed using Western blot and immunohistochemical and histopathologic analyses. For inhibition studies, we administered the STAT3-specific inhibitor, NSC74859, 90 min before ALF induction. RESULTS:We found that GABA-treated mice had substantial attenuation of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive hepatocytes and hepatocellular necrosis, decreased caspase-3, H2AX, and p38 MAPK protein levels and increased expressions of Jak2, STAT3, Bcl-2, and Mn-SOD, with improved mitochondrial integrity. The reduced apoptotic proteins led to a significantly prolonged survival after ALF induction in GABA-treated mice. The STAT3-specific inhibitor NSC74859 eliminated the survival advantage in GABA-treated mice with ALF, indicating the involvement of the STAT3 pathway in GABA-induced reduction in apoptosis. CONCLUSIONS:Our results showed that preemptive treatment with GABA protected against severe acute liver injury in mice via GABA-mediated STAT3 signaling. Preemptive administration of GABA may be a useful approach to optimize marginal donor livers before transplantation.

SUBMITTER: Hata T

PROVIDER: S-EPMC6420924 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury.

Hata Toshiyuki T Rehman Fatima F Hori Tomohide T Nguyen Justin H JH

The Journal of surgical research 20181217

<h4>Background</h4>Acute liver failure (ALF) from severe acute liver injury is a critical condition associated with high mortality. The purpose of this study was to investigate the impact of preemptive administration of γ-aminobutyric acid (GABA) on hepatic injury and survival outcomes in mice with experimentally induced ALF.<h4>Materials and methods</h4>To induce ALF, C57BL/6NHsd mice were administered GABA, saline, or nothing for 7 d, followed by intraperitoneal administration of 500 μg of tum ...[more]

PMID: 30694753

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Project description:Longitudinal alterations of gamma-aminobutyric acid (GABAA) receptor availability following traumatic brain injury have remained uncharacterized and may reflect changes in neuronal structure and function linked to cognitive recovery. We measured GABAA receptor availability using the tracer [11C]flumazenil in nine adults with traumatic brain injury (3-6 months after injury, subacute scan) and in 20 non-brain-injured individuals. A subset of subjects with traumatic brain injury (n = 7) were scanned at a second chronic time-point, 7-13 months after their first scan; controls (n = 9) were scanned for a second time, 5-11 months after the first scan. After accounting for atrophy in subjects with traumatic brain injury, we find broad decreases in GABAA receptor availability predominantly within the frontal lobes, striatum, and posterior-medial thalami; focal reductions were most pronounced in the right insula and anterior cingulate cortex (p < 0.05). Greater relative increase, compared to controls, in global GABAA receptor availability appeared between subacute and chronic scans. At chronic scan (>1 year post-injury), we find increased pallidal receptor availability compared to controls. Conversely, receptor availability remained depressed across the frontal cortices. Longitudinal improvement in executive attention correlated with increases in receptor availability across bilateral fronto-parietal cortical regions and the anterior-lateral aspects of the thalami. The specific observations of persistent bi-frontal lobe reductions and bilateral pallidal elevation are consistent with the anterior forebrain mesocircuit hypothesis for recovery of consciousness following a wide range of brain injuries; our results provide novel correlative data in support of specific cellular mechanisms underlying persistent cognitive deficits. Collectively, these measurements support the use of [11C]flumazenil to track recovery of large-scale network function following brain injuries and measure response to therapeutics.

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GABA, ?-Aminobutyric Acid, Protects Against Severe Liver Injury.

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GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury.

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