Dataset Information

Mitigation of Methimazole-Induced Hepatic Injury by Taurine in Mice.

ABSTRACT: Methimazole is the most widely prescribed antithyroid medication in humans. However, hepatotoxicity is a deleterious adverse effect associated with methimazole administration. No specific protective agent has been developed against this complication yet. This study was designed to investigate the role of taurine as a hepatoprotective agent against methimazole-induced liver injury in mice. Different reactive metabolites were proposed to be responsible for methimazole hepatotoxicity. Hence, methimazole-induced liver injury was investigated in intact and/or enzyme-induced animals in the current investigation. Animals were treated with methimazole (200 mg/kg, by gavage), and hepatic injury induced by this drug was investigated in intact and/or enzyme-induced groups. Markers such as lipid peroxidation, hepatic glutathione content, alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in plasma, and histopathological changes in the liver of animals were monitored after drug administration. Methimazole caused liver injury as revealed by increased plasma ALT. Furthermore, a significant amount of lipid peroxidation was detected in the drug-treated animals, and hepatic glutathione reservoirs were depleted. Methimazole-induced hepatotoxicity was more severe in enzyme-induced mice. The above-mentioned alterations in hepatotoxicity markers were endorsed by significant histopathological changes in the liver. Taurine administration (1 g/kg, i.p.) effectively alleviated methimazole-induced liver injury in both intact and/or enzyme-induced animals.

SUBMITTER: Heidari R

PROVIDER: S-EPMC4727863 | biostudies-other | 2015 Jan-Mar

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Mitigation of Methimazole-Induced Hepatic Injury by Taurine in Mice.

Heidari Reza R Jamshidzadeh Akram A Keshavarz Nahid N Azarpira Negar N

Scientia pharmaceutica 20140930 1

Methimazole is the most widely prescribed antithyroid medication in humans. However, hepatotoxicity is a deleterious adverse effect associated with methimazole administration. No specific protective agent has been developed against this complication yet. This study was designed to investigate the role of taurine as a hepatoprotective agent against methimazole-induced liver injury in mice. Different reactive metabolites were proposed to be responsible for methimazole hepatotoxicity. Hence, methim ...[more]

PMID: 26839807

Similar Datasets

Project description:Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia-reperfusion (I-R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the upregulation of the hepatic and systemic level of OPN in mice. Plasma aspartate aminotransferase and alanine aminotransferase levels were strongly increased in Opn(-/-) mice compared with wild-type (Wt) mice after I-R, and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNFα), interleukin 6 (IL6) and interferon-γ were strongly upregulated in Opn(-/-) mice versus Wt mice after I-R. One explanation for these responses could be the vulnerability of the OPN-deficient hepatocyte. Indeed, the downregulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen-glucose deprivation and TNFα. Further, the downregulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn(-/-) mice versus Wt mice livers after I-R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the downregulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the upregulation of iNOS, TNFα and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I-R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages.

Project description:Hepatic ischemia/reperfusion (I/R) injury is a major complication after liver transplantation, major hepatic resection, or prolonged portal vein occlusion. Furthermore, acute kidney injury is frequent after hepatic I/R and greatly increases postoperative complications. Sphinganine-1-phosphate is a sphingolipid with uncharacterized physiological effects. We serendipitously determined that plasma levels of sphinganine-1-phosphate fell significantly after liver I/R in mice. In this study, we hypothesized that repletion of plasma sphinganine-1-phosphate would protect against liver and kidney injuries after liver I/R. C57BL/6 mice were subjected to 60 min of partial hepatic I/R and treated with either vehicle or with sphinganine-1-phosphate (given immediately before and 2 h after reperfusion). Vehicle-treated mice subjected to liver I/R developed acute liver and kidney injuries with elevated plasma alanine aminotransferase and creatinine 5 and 24 h after liver I/R. However, liver and kidney injuries were significantly attenuated with sphinganine-1-phosphate treatment. Sphinganine-1-phosphate markedly inhibited liver and kidney necrosis and apoptosis 24 h after liver I/R. Moreover, sphinganine-1-phosphate attenuated neutrophil infiltration, reduced plasma IL-6 and TNF-alpha upregulation, and preserved liver and kidney vascular integrity while reducing liver and kidney F-actin degradation after liver I/R. Finally, sphinganine-1-phosphate-mediated hepatic and renal protection was blocked by VPC23019, an antagonist for sphingosine-1-phosphate type 1 receptor. Therefore, sphinganine-1-phosphate improves acute liver and kidney injuries after hepatic I/R via sphingosine-1-phosphate type 1 receptor-mediated inhibition of necrosis and apoptosis and by improving vascular integrity. Harnessing the mechanisms of cytoprotection with sphinganine-1-phosphate activation may lead to new therapies for perioperative hepatic I/R injury and subsequent remote organ injury.

Project description:BACKGROUND:Cosmic radiation exposures have been found to elicit cognitive impairments involving a wide-range of underlying neuropathology including elevated oxidative stress, neural stem cell loss, and compromised neuronal architecture. Cognitive impairments have also been associated with sustained microglia activation following low dose exposure to helium ions. Space-relevant charged particles elicit neuroinflammation that persists long-term post-irradiation. Here, we investigated the potential neurocognitive benefits of microglia depletion following low dose whole body exposure to helium ions. METHODS:Adult mice were administered a dietary inhibitor (PLX5622) of colony stimulating factor-1 receptor (CSF1R) to deplete microglia 2 weeks after whole body helium irradiation (4He, 30 cGy, 400 MeV/n). Cohorts of mice maintained on a normal and PLX5622 diet were tested for cognitive function using seven independent behavioral tasks, microglial activation, hippocampal neuronal morphology, spine density, and electrophysiology properties 4-6 weeks later. RESULTS:PLX5622 treatment caused a rapid and near complete elimination of microglia in the brain within 3 days of treatment. Irradiated animals on normal diet exhibited a range of behavioral deficits involving the medial pre-frontal cortex and hippocampus and increased microglial activation. Animals on PLX5622 diet exhibited no radiation-induced cognitive deficits, and expression of resting and activated microglia were almost completely abolished, without any effects on the oligodendrocyte progenitors, throughout the brain. While PLX5622 treatment was found to attenuate radiation-induced increases in post-synaptic density protein 95 (PSD-95) puncta and to preserve mushroom type spine densities, other morphologic features of neurons and electrophysiologic measures of intrinsic excitability were relatively unaffected. CONCLUSIONS:Our data suggest that microglia play a critical role in cosmic radiation-induced cognitive deficits in mice and, that approaches targeting microglial function are poised to provide considerable benefit to the brain exposed to charged particles.

Dataset Information

Mitigation of Methimazole-Induced Hepatic Injury by Taurine in Mice.

Publications

Mitigation of Methimazole-Induced Hepatic Injury by Taurine in Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets