Acute Liver Failure in Rats Activates Glutamine-Glutamate Cycle but Declines Antioxidant Enzymes to Induce Oxidative Stress in Cerebral Cortex and Cerebellum

Singh, Santosh; Mondal, Papia; Trigun, Surendra Kumar

doi:10.1371/journal.pone.0095855

Cited by 24 publications

(17 citation statements)

References 36 publications

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“…GSH is a tripeptide that plays important roles in maintaining reducing equivalents in the cells facing oxidative challenges (Dickinson and Forman, 2002). In the present study, GSH was remarkably decreased by TAA both in liver (Al-Attar, 2012; Amin et al, 2012) and brain (Singh et al, 2014) of MHE rats. The increased production of reactive oxygen and nitrogen oxide species (ROS/RNOS) in the brain cells, in turn, is likely to amplify the neuronal derangements associated with HE pathogenesis (Haussinger and Gorg, 2010).…”

Section: Resultssupporting

confidence: 53%

“…at 100 mg/ kg (in saline solution) thrice weekly for six weeks to induce HE as reported earlier (Singh and Trigun, 2010;Singh et al, 2014) with modification, whereas alpha-lactalbumin (Lacprodan ® alpha -10 kindly supplied from Arla food amba, Denmark) was administered orally at 100 and 150 mg/kg (in distilled water prior to use) for two weeks after induction of HE by TAA, dose selection was according to previous studies of our team (Nada, 2009;Mansour et al, 2013;Eliwa et al, 2014;Mansour et al, 2015;Nada et al, 2015). Vitamin C (L (+)-ascorbic acid, Merck Co., Darmstadt, Germany) was administered orally at 500 mg/kg for two weeks after induction of HEby TAA.…”

Section: Treatment Protocolmentioning

confidence: 94%

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Antioxidant and Hypo-Ammonemic Activities of Alpha-Lactalbumin and Vitamin C in Thioacetamide-Induced Liver and Brain Damage in Rats

Mansour¹,

Nada²,

Elmahmoudy³

et al. 2015

J App Pharm Sci

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Hepatic encephalopathy (HE) is a syndrome resulting from acute or chronic liver failure. The main hypothesis suggests a state of hyperammonemia which is responsible for both direct and indirect alterations in cerebral metabolism with increased production of reactive oxygen and nitrogen species. The effect of milk-derived alphalactalbumin (α-LAC) and vitamin C (vit. C) was evaluated in thioacetamide (TAA)-induced HEmodel in the current study. Animals were treated with TAA (100 mg/kg, i.p.) or saline thrice weekly for six weeks to induce HE then treatment groups received orally α-LAC (100 or150 mg/kg) and /or vit. C (500 mg/kg)daily for two weeks. Twenty-four hours after last treatment sera, liver and brain samples were collected to assess serum ammonia level, activities of alanine transaminase (ALT), and aspartate transaminase (AST), brain and liver oxidative stress parameters as well as histopathological investigations.TAA rats experienced increases in serum activities of ALT and AST as well as serum levels of ammonia. Furthermore, TAA induced hepatic and brain oxidative damage as indicated by increase in lipid peroxidation (LP), decrease in reduced glutathione (GSH) and decrease in superoxide dismutase (SOD) activity as well as increased nitric oxide (NO) levels. TAA caused distortion of hepatic and brain architecture as shown by histopathological examination. Treatment with α-LAC either alone or combined with vit. C resulted in improved liver functions by decline in serum AST and ALT activities and reduction in serum ammonia level. Alpha-LAC and vit. C reduced LP and NO levels while increased GSH concentration and SOD activity in hepatic and brain tissues. Finally, α-LAC-vit. C combination improved the hepatic and brain histological picture. Alpha-LAC-vit. C combination may be a promising pharmacological tool in providing a natural source of branched-chain amino acids and powerful antioxidants to combat hepatic encephalopathy-associated hyperammonemia and its consequential oxidative damage in liver and brain.

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Section: Resultssupporting

confidence: 53%

Section: Treatment Protocolmentioning

confidence: 94%

Antioxidant and Hypo-Ammonemic Activities of Alpha-Lactalbumin and Vitamin C in Thioacetamide-Induced Liver and Brain Damage in Rats

Mansour¹,

Nada²,

Elmahmoudy³

et al. 2015

J App Pharm Sci

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“…As NH 4 Ac-mediated toxicity and mortality was evident not before 4 dpf, we hypothesized that developmental alterations establishing a genetic or metabolic cascade, which is sensitive to NH 4 + , are responsible for the observed differences. Since cerebral glutamine-glutamate cycle is known to play a pivotal pathophysiological role in hyperammonemic conditions in humans [ 22 ] and was shown to be activated in a rat model of acute liver failure [ 23 ], we investigated whether glutamine synthetase and glutaminase were involved in NH 4 Ac-induced mortality. In zebrafish, three paralogs of glutamine synthetases, i.e.…”

Section: Resultsmentioning

confidence: 99%

Pharmacologic rescue of hyperammonemia-induced toxicity in zebrafish by inhibition of ornithine aminotransferase

et al. 2018

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Hyperammonemia is the common biochemical hallmark of urea cycle disorders, activating neurotoxic pathways. If untreated, affected individuals have a high risk of irreversible brain damage and mortality. Here we show that acute hyperammonemia strongly enhances transamination-dependent formation of osmolytic glutamine and excitatory glutamate, thereby inducing neurotoxicity and death in ammoniotelic zebrafish larvae via synergistically acting overactivation of NMDA receptors and bioenergetic impairment induced by depletion of 2-oxoglutarate. Intriguingly, specific and irreversible inhibition of ornithine aminotransferase (OAT) by 5-fluoromethylornithine rescues zebrafish from lethal concentrations of ammonium acetate and corrects hyperammonemia-induced biochemical alterations. Thus, OAT inhibition is a promising and effective therapeutic approach for preventing neurotoxicity and mortality in acute hyperammonemia.

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“…The results of this study showed that the MDA and PC contents were reduced in conjunction with increased levels of dietary lysine (up to a certain point), suggesting that intestinal lipid and protein damage are reduced by an optimal lysine concentration. In general, the protective ability of dietary lysine against oxidative damage may correlate with an increased antioxidant ability, which can be reflected by antioxidant enzymatic activities and non-enzymatic antioxidants [ 47 ]. In our study, an optimal dietary lysine concentration significantly increased the activities of CAT, SOD, GST, GPx, and GR, as well as the GSH level, suggesting that lysine possesses enzymatic and non-enzymatic antioxidant abilities in the intestine of fish.…”

Section: Discussionmentioning

confidence: 99%

Co- and Post-Treatment with Lysine Protects Primary Fish Enterocytes against Cu-Induced Oxidative Damage

Liu

Jiang

et al. 2016

PLoS ONE

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The aim of the work was primarily to explore the protective activity pathways of lysine against oxidative damage in fish in vivo and in enterocytes in vitro. First, grass carp were fed diets containing six graded levels of lysine (7.1–19.6 g kg-1 diet) for 56 days. Second, the enterocytes were treated with different concentrations of lysine (0–300 mg/L in media) prior to (pre-treatment), along with (co-treatment) or following (post-treatment) with 6 mg/L of Cu for 24 h. The results indicated that lysine improved grass carp growth performance. Meanwhile, lysine ameliorated lipid and protein oxidation by elevating the gene expression and activity of antioxidant enzymes (superoxide dismutase (SOD), glutathioneperoxidase (GPx), glutathione-S-transferase (GST) and reductase (GR)), and nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA levels in fish intestine. The in vitro studies showed that co- and post-treatment with lysine conferred significant protection against Cu-induced oxidative damage in fish primary enterocytes as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) OD values, along with alkaline phosphatase (ALP) and lactate dehydrogenase activities, and the depletion of protein carbonyl (PC), malondialdehyde (MDA) and 8-hydroxydeoxyguanosine contents. Moreover, lysine co-treatment decreased the activities and mRNA level of cellular SOD, GPx, GST and GR compared with the Cu-only exposed group. Gene expression of the signalling molecule Nrf2 showed the same pattern as that of SOD activity, whereas Kelch-like ECH-associated protein 1b (Keap1b) followed the opposite trend, indicating that co-treatment with lysine induced antioxidant enzymes that protected against oxidative stress through Nrf2 pathway. In addition, post-treatment with lysine increased proteasomal activity and blocked the Cu-stimulated increase in mRNA levels of GST and associated catalase (CAT) and GST activities (P<0.01 and P<0.001). GR activity and gene expression, and glutathione (GSH) content followed an opposite trend to GST activity (P<0.05). Thus, post-treatment of lysine elevated protein and DNA repair abilities and ameliorated the cellular redox state of enterocytes. The overall results suggest that lysine plays a significant role in the protection of fish intestine in vivo and in vitro through the induction of key antioxidant protection.

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Acute Liver Failure in Rats Activates Glutamine-Glutamate Cycle but Declines Antioxidant Enzymes to Induce Oxidative Stress in Cerebral Cortex and Cerebellum

Cited by 24 publications

References 36 publications

Antioxidant and Hypo-Ammonemic Activities of Alpha-Lactalbumin and Vitamin C in Thioacetamide-Induced Liver and Brain Damage in Rats

Antioxidant and Hypo-Ammonemic Activities of Alpha-Lactalbumin and Vitamin C in Thioacetamide-Induced Liver and Brain Damage in Rats

Pharmacologic rescue of hyperammonemia-induced toxicity in zebrafish by inhibition of ornithine aminotransferase

Co- and Post-Treatment with Lysine Protects Primary Fish Enterocytes against Cu-Induced Oxidative Damage

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