Assessment of drug-induced mitochondrial dysfunctions is important in drug development as well as in the understanding of molecular mechanism of therapeutic or adverse effects of drugs. The aim of this study was to investigate the effects of three typical antipsychotics (APs) and seven atypical APs on mitochondrial bioenergetics. The effects of selected APs on citrate synthase, electron transport chain complexes (ETC), and mitochondrial complex I- or complex II-linked respiratory rate were measured using mitochondria isolated from pig brain. Complex I activity was decreased by chlorpromazine, haloperidol, zotepine, aripiprazole, quetiapine, risperidone, and clozapine. Complex II + III was significantly inhibited by zotepine, aripiprazole, quetiapine, and risperidone. Complex IV was inhibited by zotepine, chlorpromazine, and levomepromazine. Mitochondrial respiratory rate was significantly inhibited by all tested APs, except for olanzapine. Typical APs did not exhibit greater efficacy in altering mitochondrial function compared to atypical APs except for complex I inhibition by chlorpromazine and haloperidol. A comparison of the effects of APs on individual respiratory complexes and on the overall mitochondrial respiration has shown that mitochondrial functions may not fully reflect the disruption of complexes of ETC, which indicates AP-induced modulation of other mitochondrial proteins. Due to the complicated processes associated with mitochondrial activity, it is necessary to measure not only the effect of the drug on individual mitochondrial enzymes but also the respiration rate of the mitochondria or a similar complex process. The experimental approach used in the study can be applied to mitochondrial toxicity testing of newly developed drugs.

• MeSH
• antipsychotika toxicita   MeSH
• energetický metabolismus účinky léků   MeSH
• mitochondrie účinky léků   patologie   MeSH
• mozek účinky léků   metabolismus   MeSH
• prasata MeSH
• respirační komplex I účinky léků   metabolismus   MeSH
• respirační komplex II účinky léků   metabolismus   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

PURPOSE: Despite the significant interest in molecular hydrogen as an antioxidant in the last eight years, its quantitative metabolic parameters in vivo are still lacking, as is an appropriate method for determination of hydrogen effectivity in the mammalian organism under various conditions. BASIC PROCEDURES: Intraperitoneally-applied deuterium gas was used as a metabolic tracer and deuterium enrichment was determined in the body water pool. Also, in vitro experiments were performed using bovine heart submitochondrial particles to evaluate superoxide formation in Complex I of the respiratory chain. MAIN FINDINGS: A significant oxidation of about 10% of the applied dose was found under physiological conditions in rats, proving its antioxidant properties. Hypoxia or endotoxin application did not exert any effect, whilst pure oxygen inhalation reduced deuterium oxidation. During in vitro experiments, a significant reduction of superoxide formation by Complex I of the respiratory chain was found under the influence of hydrogen. The possible molecular mechanisms of the beneficial effects of hydrogen are discussed, with an emphasis on the role of iron sulphur clusters in reactive oxygen species generation and on iron species-dihydrogen interaction. PRINCIPAL CONCLUSIONS: According to our findings, hydrogen may be an efficient, non-toxic, highly bioavailable and low-cost antioxidant supplement for patients with pathological conditions involving ROS-induced oxidative stress.

• MeSH
• antioxidancia metabolismus   farmakologie   MeSH
• ascitická tekutina metabolismus   MeSH
• deuterium farmakokinetika   MeSH
• endotoxiny farmakologie   MeSH
• hyperoxie metabolismus   MeSH
• hypoxie metabolismus   MeSH
• krysa rodu rattus MeSH
• oxid uhelnatý analýza   MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• preklinické hodnocení léčiv MeSH
• respirační komplex I účinky léků   metabolismus   MeSH
• respirační vzplanutí účinky léků   MeSH
• scavengery volných radikálů metabolismus   farmakologie   MeSH
• skot MeSH
• srdeční mitochondrie metabolismus   MeSH
• superoxidy metabolismus   MeSH
• tělesná voda metabolismus   MeSH
• tkáňová distribuce MeSH
• vodík metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• skot MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic condition of the liver in the western world. There is only little evidence about altered sensitivity of steatotic liver to acute toxic injury. The aim of this project was to test whether hepatic steatosis sensitizes rat liver to acute toxic injury induced by thioacetamide (TAA). Male Sprague-Dawley rats were fed ad libitum a standard pelleted diet (ST-1, 10% energy fat) and high-fat gelled diet (HFGD, 71% energy fat) for 6 weeks and then TAA was applied intraperitoneally in one dose of 100 mg/kg. Animals were sacrificed in 24-, 48- and 72-h interval after TAA administration. We assessed the serum biochemistry, the hepatic reduced glutathione, thiobarbituric acid reactive substances, cytokine concentration, the respiration of isolated liver mitochondria and histopathological samples (H+E, Sudan III, bromodeoxyuridine [BrdU] incorporation). Activities of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase and concentration of serum bilirubin were significantly higher in HFGD groups after application of TAA, compared to ST-1. There were no differences in activities of respiratory complexes I and II. Serum tumour necrosis factor alpha at 24 and 48 h, liver tissue interleukin-6 at 72 h and transforming growth factor β1 at 24 and 48 h were elevated in TAA-administrated rats fed with HFGD, but not ST-1. TAA-induced centrilobular necrosis and subsequent regenerative response of the liver were higher in HFGD-fed rats in comparison with ST-1. Liver affected by NAFLD, compared to non-steatotic liver, is more sensitive to toxic effect of TAA.

• MeSH
• cholesterol metabolismus   MeSH
• cytokiny krev   MeSH
• dietní tuky škodlivé účinky   MeSH
• játra účinky léků   metabolismus   patologie   MeSH
• karcinogeny toxicita   MeSH
• krysa rodu rattus MeSH
• látky reagující s kyselinou thiobarbiturovou metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• potkani Sprague-Dawley MeSH
• proliferace buněk účinky léků   MeSH
• respirační komplex I účinky léků   fyziologie   MeSH
• respirační komplex II účinky léků   fyziologie   MeSH
• thioacetamid toxicita   MeSH
• triglyceridy metabolismus   MeSH
• ztučnělá játra krev   chemicky indukované   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Our previous work demonstrated the marked decrease of mitochondrial complex I activity in the cerebral cortex of immature rats during the acute phase of seizures induced by bilateral intracerebroventricular infusion of dl-homocysteic acid (600 nmol/side) and at short time following these seizures. The present study demonstrates that the marked decrease ( approximately 60%) of mitochondrial complex I activity persists during the long periods of survival, up to 5 weeks, following these seizures, i.e. periods corresponding to the development of spontaneous seizures (epileptogenesis) in this model of seizures. The decrease was selective for complex I and it was not associated with changes in the size of the assembled complex I or with changes in mitochondrial content of complex I. Inhibition of complex I was accompanied by a parallel, up to 5 weeks lasting significant increase (15-30%) of three independent mitochondrial markers of oxidative damage, 3-nitrotyrosine, 4-hydroxynonenal and protein carbonyls. This suggests that oxidative modification may be most likely responsible for the sustained deficiency of complex I activity although potential role of other factors cannot be excluded. Pronounced inhibition of complex I was not accompanied by impaired ATP production, apparently due to excess capacity of complex I documented by energy thresholds. The decrease of complex I activity was substantially reduced by treatment with selected free radical scavengers. It could also be attenuated by pretreatment with (S)-3,4-DCPG (an agonist for subtype 8 of group III metabotropic glutamate receptors) which had also a partial antiepileptogenic effect. It can be assumed that the persisting inhibition of complex I may lead to the enhanced production of reactive oxygen and/or nitrogen species, contributing not only to neuronal injury demonstrated in this model of seizures but also to epileptogenesis.

• MeSH
• agonisté excitačních aminokyselin farmakologie   MeSH
• aldehydy metabolismus   MeSH
• časové faktory MeSH
• down regulace účinky léků   fyziologie   MeSH
• energetický metabolismus účinky léků   fyziologie   MeSH
• epilepsie metabolismus   patofyziologie   MeSH
• homocystein analogy a deriváty   toxicita   MeSH
• konvulziva toxicita   MeSH
• krysa rodu rattus MeSH
• metabolické sítě a dráhy fyziologie   MeSH
• míra přežití MeSH
• mitochondriální nemoci chemicky indukované   metabolismus   patofyziologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• mozková kůra metabolismus   patologie   patofyziologie   MeSH
• novorozená zvířata MeSH
• oxidační stres účinky léků   fyziologie   MeSH
• potkani Wistar MeSH
• respirační komplex I účinky léků   metabolismus   MeSH
• scavengery volných radikálů farmakologie   MeSH
• tyrosin analogy a deriváty   metabolismus   MeSH
• záchvaty chemicky indukované   metabolismus   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH