Oxidative stress and tissue pathology caused by subacute exposure to ammonium acetate in rats and their response to treatments with alpha-ketoglutarate and N-acetyl cysteine

Abstract

Ammonia is a widely used industrial chemical that is recognized as a potent neurotoxin and environmental pollutant. The present study addresses the oxidative stress and tissue pathology caused by 4 weeks of exposure to ammonium acetate (AMA; 100 mg/kg daily; orally) in rats, and their response to oral treatments with alpha-ketoglutarate (A-KG; 1.0 g/kg), a potential cyanide antidote, and/or N-acetyl cysteine (NAC; 10 mg/kg), an antioxidant. The organ-body weight index of brain and liver was significantly increased by AMA but kidney was unaffected. Also, plasma ammonia levels were significantly elevated without any concomitant change in blood gas status and hematology but levels of catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and reduced glutathione (GSH) in the brain and liver were diminished, accompanied by elevated levels of malondialdehyde. Levels of glutathione disulfide (GSSG) were unaffected, but the ratio of GSH:GSSG was reduced. Plasma alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and total bilirubin were raised but urea, uric acid and creatinine levels were not altered. AMA also caused temporal, hepatic and renal pathology. However, the renal pathology was not supported by any biochemical alterations. A-KG or NAC alone afforded less protection against AMA as compared to both given together. The protective efficacy of A-KG can be ascribed to its ability to detoxify ammonia and additionally both A-KG and NAC have antioxidant properties as well. The study suggests a new therapeutic regimen for ammonia poisoning.

Ammonia toxicity: from head to toe?

“…In fact, oxidative stress can also cause renal ammoniagenesis which may contribute to progression of renal injury (Dan et al, 2008). By contrast, a very recent study by Satpute et al observed that subacute exposure to ammonium acetate in rats induces renal necrosis and tubular degeneration, which were not correlated with either oxidative or biochemical changes (Satpute et al, 2014). Indeed, it is apparent that exposure of neutrophils to ammonia impair phagocytosis and promotes increased reactive oxygen species generation that results in oxidative stress at infection sites and collateral damage to host tissue (Shawcross et al, 2008).…”

Changes of the Thioredoxin System, Glutathione Peroxidase Activity and Total Antioxidant Capacity in Rat Brain Cortex During Acute Liver Failure: Modulation by l-histidine

“…On the other hand, a significant decrease was observed in the brain mitochondria during ALF in rats [ 15 ]. Depending on the HA or ALF model employed, the brain activity of the key GSH-metabolizing enzyme, glutathione peroxidase (GPx) was noted to either go up [ 16 ] or down [ 17 , 18 ].…”

Dietary α‐ketoglutarate supplementation improves hepatic and intestinal energy status and anti‐oxidative capacity of Cherry Valley ducks

“…In the LPS-challenged piglets, AKG supplementation at 1% elevated GSH-Px activity and tended to reduce MDA content in the liver (Wang et al 2015). In a rat model of ammonium poisoning, AKG showed antioxidant properties for the protection of the liver (Satpute et al 2014). In a rat model of ammonium poisoning, AKG showed antioxidant properties for the protection of the liver (Satpute et al 2014).…”

“…As an antidote for cyanogen, post-treatment with AKG abrogated cyanogen-induced oxidative damage in the plasma, brain, liver and kidney of rats (Bhattacharya et al 2014). In a rat model of ammonium poisoning, AKG showed antioxidant properties for the protection of the liver (Satpute et al 2014). It has been reported that AKG could detoxify excess ammonia, participate in non-enzymatic oxidative decarboxylation during hydrogen peroxide decomposition, and enhance the proper metabolism of fats, resulting in reduced generation of oxygen radicals and diminished lipid peroxidative damages (Velvizhi et al 2002).…”