title: Carnosine Reduces Oxidative Stress and Reverses Attenuation of Righting and Postural Reflexes in Rats with Thioacetamide-Induced Liver Failure.
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.
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Milewski
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Hilgier
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland.
authors.forename: Inez
authors.initials: I
authors.lastname: Fręśko
authors.affiliation: Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Polowy
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Podsiadłowska
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Zołocińska
authors.affiliation: Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland.
authors.forename: Aneta W
authors.initials: AW
authors.lastname: Grymanowska
authors.affiliation: Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Filipkowski
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Albrecht
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland. mzielinska@imdik.pan.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zielińska
mesh_terms: D000818:Animals; D002336:Carnosine / Q000494:pharmacology*; D017093:Liver Failure / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D011187:Posture; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide / Q000633:toxicity*
chemical_list: D013853:Thioacetamide; D002336:Carnosine
keywords: Carnosine; Hepatic encephalopathy; Histidine; Neuroprotection; Oxidative stress; Postural reflex; Righting reflex