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

Abstract

Glutathione and thioredoxin are complementary antioxidants in the protection of mammalian tissues against oxidative–nitrosative stress (ONS), and ONS is a principal cause of symptoms of hepatic encephalopathy (HE) associated with acute liver failure (ALF). We compared the activities of the thioredoxin system components: thioredoxin (Trx), thioredoxin reductase (TrxR) and the expression of the thioredoxin-interacting protein, and of the key glutathione metabolizing enzyme, glutathione peroxidase (GPx) in the cerebral cortex of rats with ALF induced by thioacetamide (TAA). ALF increased the Trx and TrxR activity without affecting Trip protein expression, but decreased GPx activity in the brains of TAA-treated rats. The total antioxidant capacity (TAC) of the brain was increased by ALF suggesting that upregulation of the thioredoxin may act towards compensating impaired protection by the glutathione system. Intraperitoneal administration of l-histidine (His), an amino acid that was earlier reported to prevent acute liver failure-induced mitochondrial impairment and brain edema, abrogated most of the acute liver failure-induced changes of both antioxidant systems, and significantly increased TAC of both the control and ALF-affected brain. These observations provide further support for the concept of that His has a potential to serve as a therapeutic antioxidant in HE. Most of the enzyme activity changes evoked by His or ALF were not well correlated with alterations in their expression at the mRNA level, suggesting complex translational or posttranslational mechanisms of their modulation, which deserve further investigations.

Carnosine Reduces Oxidative Stress and Reverses Attenuation of Righting and Postural Reflexes in Rats with Thioacetamide-Induced Liver Failure

“…2 ). In agreement with earlier reported data [ 26 ], the total antioxidant capacity (TAC) in brain homogenates from TAA rats was increased by ~50 %. While administration of His or Car did not affect TAC in control brains, each potentiated TAC in TAA -affected brain (Fig.…”

“…However, His is also known for its antioxidant action [ 23 , 24 ]. Moreover, studies from our laboratory have shown that His also prevents reduction of glutathione content in brain mitochondria of TAA rats [ 25 ] and increases the total antioxidant capacity (TAC) of TAA rat brain [ 26 ]. In the same TAA model of HE, intraperitoneal (i.p.)…”

The dimethylarginine (ADMA)/nitric oxide pathway in the brain and periphery of rats with thioacetamide-induced acute liver failure: Modulation by histidine

“…His was suggested to exert these effects by inhibiting mitochondrial Gln transport. Alternatively, the protective properties of His could be due to its antioxidative potential of this amino acid as noted both in the central nervous system (CNS) and in non CNS tissues in different conditions (Wade and Tucker, 1998), and recently confirmed in the TAA model of HE (Ruszkiewicz and Albrecht, 2014;Ruszkiewicz et al, 2013). The decrease of ADMA concentration evoked by His in TAA rat model of ALF could be most likely due to one, or the combination, of the following events: (i) changes in DDAH activity and/or expression, (ii) inter-cellular or blood-brain barrier ADMA transport.…”

Redox-Driven Signaling: 2-Oxo Acid Dehydrogenase Complexes as Sensors and Transmitters of Metabolic Imbalance

“…Thus, in vitro data on the redox exchange between mitochondrial thioredoxin and the complex-bound dihydrolipoyl residues are supported by the consequences of genetic or pharmacological manipulations affecting cellular redox state and viability. As shown in the next sections, the interaction of the dihydrolipoyl residues with thioredoxin may transmit the signal on perturbed homeostasis from the 2-oxo acid dehydrogenase complexes to thiol-based peroxidases (peroxiredoxins) and a thioredoxin-interacting protein regulating mitochondrial function in mammals (164,212).…”