Abstract
Cerebral oxidative stress (OS) contributes to the pathogenesis of hepatic encephalopathy (HE). Existing evidence suggests that systemic administration of l-histidine (His) attenuates OS in brain of HE animal models, but the underlying mechanism is complex and not sufficiently understood. Here we tested the hypothesis that dipeptide carnosine (β-alanyl-l-histidine, Car) may be neuroprotective in thioacetamide (TAA)-induced liver failure in rats and that, being His metabolite, may mediate the well documented anti-OS activity of His. Amino acids [His or Car (100 mg/kg)] were administrated 2 h before TAA (i.p., 300 mg/kg 3× in 24 h intervals) injection into Sprague–Dawley rats. The animals were thus tested for: (i) brain prefrontal cortex and blood contents of Car and His, (ii) amount of reactive oxygen species (ROS), total antioxidant capacity (TAC), GSSG/GSH ratio and thioredoxin reductase (TRx) activity, and (iii) behavioral changes (several models were used, i.e. tests for reflexes, open field, grip test, Rotarod). Brain level of Car was reduced in TAA rats, and His administration significantly elevated Car levels in control and TAA rats. Car partly attenuated TAA-induced ROS production and reduced GSH/GSSG ratio, whereas the increase of TRx activity in TAA brain was not significantly modulated by Car. Further, Car improved TAA-affected behavioral functions in rats, as was shown by the tests of righting and postural reflexes. Collectively, the results support the hypothesis that (i) Car may be added to the list of neuroprotective compounds of therapeutic potential on HE and that (ii) Car mediates at least a portion of the OS-attenuating activity of His in the setting of TAA-induced liver failure.
Highlights
Acute or chronic liver failure leads to the development of hepatic encephalopathy (HE) [1] which is currently defined as a complex neuropsychiatric syndrome in which an increase of blood and brain ammonia concentration seems to be a main causative factor [2,3,4]
Pathogenesis of HE is associated with oxidative stress (OS) [8, 43], which mainly results from inefficient clearance of reactive oxygen species (ROS) by natural defense systems composed of enzymatic and non-enzymatic anti-oxidants [44, 45]
We tested the therapeutic potential of systematically administered of one other potential antioxidant, b-alanyl-L-histidine (Car) in a well-established TAA model reproducing cerebral metabolic changes and symptoms of acute HE [28]
Summary
Acute or chronic liver failure leads to the development of HE [1] which is currently defined as a complex neuropsychiatric syndrome in which an increase of blood and brain ammonia concentration seems to be a main causative factor [2,3,4]. In both humans suffering from HE and animals with induced HE, brain edema is a dominating fatal consequence of elevated ammonia and other pathogens involved (e.g. inflammation, hyponatremia, hemorrhage, etc.) [5, 6]. We carried behavioral tests, analyzing cognitive and motor functions which are typically impaired in the setting of HE [17, 18]
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