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.

Fig. 1

Effect of ALF in the TAA model (TAA) or/and histidine (His) administration on glutathione peroxidase (GPx) activity (a, n = 6) and glutathione peroxidase 1 (GPx1) mRNA level (b, n = 7–8) in rat brain cortex. Results are mean values ± SD. *p < 0.05, **p < 0.01, ***p < 0.001 versus Control, ^### p < 0.001 versus TAA, ^$$$ p < 0.001 versus His

Fig. 2

Effect of ALF in the TAA model (TAA) or/and histidine (His) administration on thioredoxin reductase (TrxR) activity (a, n = 4–5), thioredoxin reductase 1 (TrxR1) (b, n = 6), thioredoxin reductase 2 (TrxR2) (c, n = 6–7) mRNA level and TrxR1 protein level (d, n = 6) in rat brain cortex. Results are mean values ± SD. *p < 0.05, **p < 0.01, ***p < 0.001 versus Control, ^# p < 0.05, ^## p < 0.01, ^### p < 0.001 versus TAA

Fig. 3

Effect of ALF in the TAA model (TAA) or/and histidine (His) administration on thioredoxin (Trx) activity (a, n = 4–5), and the expression of mRNAs coding Trx1 (b, n = 7–8) and Trx2 (c, n = 7–8) in rat brain cortex. Results are mean values ± SD. *p < 0.05, **p < 0.01, ***p < 0.001 versus Control, ^# p < 0.05, ^### p < 0.001 versus TAA

Fig. 4

Effect of ALF in the TAA model (TAA) or/and histidine (His) administration on thioredoxin-interacting protein (Trxip) protein (a, n = 6–7) and mRNA level (b, n = 6–8) in rat brain cortex. Results are mean values ± SD. *p < 0.05, ***p < 0.001 versus Control, ^### p < 0.001 versus TAA, ^$$$ p < 0.001 versus His

Fig. 5

Effect of ALF in the TAA model (TAA) or/and histidine (His) administration on total antioxidant capacity in rat brain cortex. Results are mean (n = 3–4) values ± SD. **p < 0.01 versus Control