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Biomedical subjects

E Serbinova

Publications and source records attributed to E Serbinova.

At least 19 recordsLinked to original sources
PubMed1996

Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats.

This study revealed a marked stereospecificity in the prevention of buthionine sulfoximine-induced cataract, and in the protection of lens antioxidants, in newborn rats by alpha-lipoate, R- and racemic alpha-lipoate decreased cataract formation from 100% (buthionine sulfoximine only) to 55% (buthionine sulfoximine + R-alpha-lipoic acid) and 40% (buthionine sulfoximine + rac-alpha-lipoic acid) (p<0.05 compared to buthionine sulfoximine only). S-alpha-lipoic acid had no effect on cataract formation induced by buthionine sulfoximine. The lens antioxidants glutathione, ascorbate, and vitamin E were depleted to 45, 62, and 23% of control levels, respectively, by buthionine sulfoximine treatment, but were maintained at 84-97% of control levels when R-alpha-lipoic acid or rac-alpha-lipoic acid were administered with buthionine sulfoximine; S-alpha-lipoic acid administration had no protective effect on lens antioxidants. When enantiomers of alpha-lipoic acid were administered to animals, R-alpha-lipoic acid was taken up by lens and reached concentrations 2- to 7-fold greater than those of S-alpha-lipoic acid, with rac-alpha-lipoic acid reaching levels midway between the R-isomer and racemic form. Reduced lipoic acid, dihydrolipoic acid, reached the highest levels in lens of the rac-alpha-lipoic acid-treated animals and the lowest levels in S-alpha-lipoic acid-treated animals. These results indicate that the protective effects of alpha-lipoic acid against buthionine sulfoximine-induced cataract are probably due to its protective effects on lens antioxidants, and that the stereospecificity exhibited is due to selective uptake and reduction of R-alpha-lipoic acid by lens cells.

Animals↗
PubMed1995

Alpha-lipoic acid prevents buthionine sulfoximine-induced cataract formation in newborn rats.

We investigated the effect of alpha-lipoic acid, a powerful antioxidant, on cataract formation in L-buthionine(S,R)-sulfoximine (BSO)-treated newborn rats and found that a dose of 25 mg/kg b.w. protected 60% of animals from cataract formation. L-buthionine(S,R)-sulfoximine is an inhibitor of glutathione synthesis, whose administration to newborn animals leads to the development of cataracts; this is a potential model for studying the role of therapeutic antioxidants in protecting animals from cataract formation. Major biochemical changes in the lens associated with the protective effect of alpha-lipoic acid were increases in glutathione, ascorbate, and vitamin E levels, loss of which are effects of BSO administration. Treatment with alpha-lipoic acid also restored the activities of glutathione peroxidase, catalase, and ascorbate free radical reductase in lenses of L-buthionine(S,R)-sulfoximine-treated animals but did not affect glutathione reductase or superoxide dismutase activity. We conclude that alpha-lipoic acid may take over some of the functions of glutathione (e.g., maintaining the higher level of ascorbate, indirect participation in vitamin E recycling); the increase of glutathione level in lens tissue mediated by lipoate could be also due to a direct protection of protein thiols. Thus, alpha-lipoic acid could be of potential therapeutic use in preventing cataracts and their complications.

Animals↗
PubMed1995

Modelling cortical cataractogenesis 17: in vitro effect of a-lipoic acid on glucose-induced lens membrane damage, a model of diabetic cataractogenesis.

The effect of R, S, and racemic forms of a-lipoic acid was tested on the formation of opacity in normal rat lenses incubated with 55.6 mM glucose, as a model for in vivo diabetic cataractogenesis. Control lenses, incubated 8 days with 5.56 mM glucose, did not develop opacities. Formation of lens opacities in vitro was correlated with lactate dehydrogenase (LDH) leakage into the incubation medium. Opacity formation and LDH leakage, resulting from incubation in medium containing 55.6 mM glucose to model diabetes, were both suppressed by the addition of 1 mM R-lipoic acid. Addition of 1 mM racemic lipoic acid reduces these damaging effects to the lens by one-half, while S-lipoic acid potentiated LDH leakage, consistent with the hypothesis that R-lipoic acid is the active form. Although HPLC analysis demonstrated that both stereoisomers of lipoic acid were reduced to dihydrolipoate at comparable rates by the intact lens, the mitochondrial lipoamide dehydrogenase system is highly specific for reduction of exogenous R-lipoic to dihydrolipoic acid. Therefore, stereospecific protection against this opacity is consistent with specific reduction of R-lipoic acid in mitochondria of the vulnerable cells at the lens equator where the first globular degeneration is seen in glucose cataract.

Animals↗
PubMed1993

Interaction of the pyridoindole stobadine with peroxyl, superoxide and chromanoxyl radicals.

The pyridoindole derivative stobadine [(-)-cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido(4,3b)indole] has been described as a drug with antihypoxic and antiarrhythmic cardioprotective properties. Here its reactivity with peroxyl radicals in liposomes using a lipid-soluble azo-initiator of peroxyl radicals, 2,2'-azo-bis(2,4-dimethyl-valeronitrile) (AMVN), was examined. Stobadine exerted scavenging as evidenced by the inhibition of: (i) cis-parinaric acid fluorescence decay (half-maximal effect at 20 microM), or (ii) luminol-sensitized chemiluminescence (half-maximal effect at 33 microM). In rat liver microsomes, stobadine was equally efficient in inhibiting lipid peroxidation induced by lipid-soluble (AMVN) or water-soluble 2,2'-azo-bis(2-aminopropane)-HCl (AAPH), azo-initiators of peroxyl radicals with half-maximal effect at 17 microM. Stobadine partitions in a two-phase system (octanol-water) with the coefficient log P = 0.57 +/- 0.03, explaining its ability to quench peroxyl radicals in both lipid and aqueous phases. Stobadine is not an efficient scavenger of superoxide radicals. The second order rate constant for the reaction of stobadine with superoxide was estimated to be 7.5 x 10(2) M-1 sec-1 as measured by superoxide-induced lucigenin-amplified chemiluminescence. ESR measurements showed that stobadine in liposomes does not reduce the chromanoxyl radical of a vitamin E homologue with a 6-carbon side-chain, 2,5,7,8-tetramethyl-2-(4'-methylpentyl)chroman-6-ol(chromanol++ +-alpha-C6), in agreement with pulse-radiolysis results obtained using Trolox in homogeneous solution (Steenken et al., Chem Res Toxicol 5: 355-360, 1992). Stobadine increased the magnitude of the chromanoxyl and ascorbyl radical ESR signal generated by lipoxygenase+arachidonate. This was interpreted to be due to the interaction of stobadinyl radicals with the chromanol ring and ascorbate, respectively. It is suggested that high reactivity of stobadine radicals requires the presence of reducing antioxidants (vitamin E, vitamin C) to exhibit its antioxidant effects in physiological systems.

Amidines↗
PubMed1993

Nitecapone protects the Langendorff perfused heart against ischemia-reperfusion injury.

We assessed the protection afforded against myocardial ischemia/reperfusion by nitecapone in the Langendorff heart model using male Sprague-Dawley rats. We found that when present in the perfusate 10 microM nitecapone improved the mechanical function of the heart and lowered the enzyme leakage of lactate dehydrogenase after 40 minutes of global ischemia. In nitecapone treated hearts the content of oxidized proteins and lipids (carbonyl groups and endogenous lipid fluorescent products) decreased. Nitecapone partially prevented the loss of total sulfhydryl groups and vitamin E after ischemia and reperfusion. We suggest that the mechanism of nitecapone protection most likely involves direct antioxidant action and enhancing the activity of other antioxidants.

Animals↗
PubMed1992

Dihydrolipoic acid--a universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals.

Thioctic (lipoic) acid is used as a therapeutic agent in a variety of diseases in which enhanced free radical peroxidation of membrane phospholipids has been shown to be a characteristic feature. It was suggested that the antioxidant properties of thioctic acid and its reduced form, dihydrolipoic acid, are at least in part responsible for the therapeutic potential. The reported results on the antioxidant efficiency of thioctic and dihydrolipoic acids obtained in oxidation models with complex multicomponent initiation systems are controversial. In the present work we used relatively simple oxidation systems to study the antioxidant effects of dihydrolipoic and thioctic acids based on their interactions with: (1) peroxyl radicals which are essential for the initiation of lipid peroxidation, (2) chromanoxyl radicals of vitamin E, and (3) ascorbyl radicals of vitamin C, the two major lipid- and water-soluble antioxidants, respectively. We demonstrated that: (1) dihydrolipoic acid (but not thioctic acid) was an efficient direct scavenger of peroxyl radicals generated in the aqueous phase by the water-soluble azoinitiator 2,2'-azobis(2-amidinopropane)-dihydrochloride, and in liposomes or in microsomal membranes by the lipid-soluble azoinitiator 2,2'-azobis(2,4-dimethylvaleronitrile); (2) both dihydrolipoic acid and thioctic acid did not interact directly with chromanoxyl radicals of vitamin E (or its synthetic homologues) generated in liposomes or in the membranes by three different ways: UV-irradiation, peroxyl radicals of 2,2'-azobis(2,4-dimethylvaleronitrile), or peroxyl radicals of linolenic acid formed by the lipoxygenase-catalyzed oxidation; and (3) dihydrolipoic acid (but not thioctic acid) reduced ascorbyl radicals (and dehydroascorbate) generated in the course of ascorbate oxidation by chromanoxyl radicals. This interaction resulted in ascorbate-mediated dihydrolipoic acid-dependent reduction of the vitamin E chromanoxyl radicals, i.e. vitamin E recycling. We conclude that dihydrolipoic acid may act as a strong direct chain-breaking antioxidant and may enhance the antioxidant potency of other antioxidants (ascorbate and vitamin E) in both the aqueous and the hydrophobic membraneous phases.

Animals↗
PubMed1992

Succinate-ubiquinone reductase linked recycling of alpha-tocopherol in reconstituted systems and mitochondria: requirement for reduced ubiquinone.

Studies have demonstrated that accumulation of mitochondrial tocopheroxyl radical, the primary oxidation product of alpha-tocopherol, accompanies rapid consumption of tocopherol. Enzyme-linked electron flow lowers both the steady-state concentration of the radical and the consumption of tocopherol. Reduction of tocopheroxyl radical by a mitochondrial electron carrier(s) seems a likely mechanism of tocopherol recycling. Succinate-ubiquinone reductase (complex II) was incorporated into liposomes in the presence of tocopherol and ubiquinone-10. After inducing formation of tocopheroxyl radical, it was possible to show that reduced ubiquinone prevents radical accumulation and tocopherol consumption. There was no evidence of direct reduction of tocopheroxyl radical by succinate-reduced complex II. These reactions were also measured using ubiquinone-1 and alpha-C-6-chromanol (2,5,7,8-tetramethyl-2-(4'-methylpentyl)-6-chromanol) which are less hydrophobic analogues of ubiquinone-10 and alpha-tocopherol. Mitochondrial membranes were made deficient in ubiquinone but sufficient in alpha-tocopherol and were reconstituted with added quinone. With these membranes it was shown that mitochondrial enzyme-linked reduction of ubiquinone protects alpha-tocopherol from consumption, and there is a requirement for ubiquinone. This complements the observations made in liposomes and we propose that reduced mitochondrial ubiquinones have a role in alpha-tocopherol protection, presumably through efficient reduction of the tocopheroxyl radical.

Animals↗
PubMed1992

Thioctic acid protects against ischemia-reperfusion injury in the isolated perfused Langendorff heart.

Antioxidant properties of thioctic and dihydrolipoic acid have been demonstrated in membranes and low density lipoproteins (LDL) in vitro. In vivo studies with dietary supplementation of thioctic acid to rats showed that it can also protect tissues against oxidative damage. Presumably, this action is due to a thioctic acid dihydrolipoic acid (TA/DHLA) coupled antioxidant mechanism, which enhances the activity of other antioxidants (i.e. ascorbate, alpha-tocopherol) by regenerating them from their radical form. In the present study, thioctic acid proved to protect against ischemia/reperfusion injury to Langendorff perfused hearts. Hearts isolated from rats fed thioctic acid and subjected to ischemia exhibited better mechanical recovery (left ventricular developed pressure) after reperfusion and lower lactate dehydrogenase leakage. Thioctic acid supplementation also decreased the appearance of fluorescent lipid peroxidation products after ischemia/reperfusion, lowered the rate of 2,2'-azobis-(2,4-dimethylvaleronitrile) (AMVN) induced lipid peroxidation in heart homogenates, and prevented the loss of alpha-tocopherol. The total sulfhydryl group content in thioctic acid fed animals was higher and the decrease due to ischemia-reperfusion was not as marked in this group as observed in the control. These results show that dietary supplementation with thioctic acid in vivo provides protection against ischemia/reperfusion injury in the Langendorff heart model.

Animals↗
PubMed1992

Distribution and antioxidant activity of a palm oil carotene fraction in rats.

The aim of this study was to determine the tissue distribution of carotenoids in palm oil and to correlate the accumulation of carotenoids with protection against oxidative stress. We found that: (i) After 2 weeks beta-carotene in the liver increased from 7.3 to 30 ng/g wet tissue; alpha-carotene and lycopene after 10 weeks of feeding were 74 and 49 ng/g wet tissue respectively; (ii) Beta-carotene content in heart and hind limb skeletal muscles increased after 10 weeks to 17 and 6 ng/g wet tissue respectively; (iii) No carotenoids were detected in the brain, adipose and skin during the period of feeding; (iv) After in vitro induction of lipid peroxidation in liver homogenates by an azo-initiator of peroxyl radicals an inverse correlation between tissue carotenoid level and accumulation of lipid peroxidation products was observed; alpha-carotene > lycopene > beta-carotene.

Adipose Tissue↗
PubMed1991

Free radical scavenging is involved in the protective effect of L-propionyl-carnitine against ischemia-reperfusion injury of the heart.

L-Propionyl-carnitine is known to improve the recovery of myocardial function and metabolic parameters reduced in the course of ischemia-reperfusion of the heart. The mechanism of this protective effect of L-propionyl-carnitine is not fully understood. The purpose of this study was to elucidate the effects of L-propionyl-carnitine in Langendorff perfused rat hearts subjected to 40 min of ischemia followed by 20 min of reperfusion. We tested the hypothesis that L-propionyl-carnitine suppresses generation of oxygen radicals and subsequent oxidative modification of myocardial proteins during reperfusion. Our data show that the protective effect of L-propionyl-carnitine in the course of ischemia-reperfusion is highly significant in terms both of mechanical properties of the heart (developed pressure) and of high-energy phosphates (ATP, creatine phosphate). Myocardial creatine phosphokinase (CPK) activity decreased in the course of the reperfusion period. The loss of CPK activity was partially prevented by L-propionyl-carnitine. Two other effects were observed when L-propionyl-carnitine was present in the perfusion solution: (i) the reperfusion-induced sharp increase in oxidative protein modification was completely prevented as detected by the formation of protein carbonyls, and (ii) generation of hydroxyl radicals was significantly inhibited as detected by the formation of the adducts with the spin trap 5,5-dimethyl-1-pyrroline-1-oxide. We conclude that the protective effect of L-propionyl-carnitine against ischemia-reperfusion injury of the heart is at least due in part to its ability to suppress the development of oxidative stress and free radical damage.

Adenosine Triphosphate↗
PubMed1991

Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol.

d-Alpha-tocopherol (2R,4'R,8'R-Alpha-tocopherol) and d-alpha-tocotrienol are two vitamin E constituents having the same aromatic chromanol "head" but differing in their hydrocarbon "tail": tocopherol with a saturated and toctrienol with an unsaturated isoprenoid chain. d-Alpha-tocopherol has the highest vitamin E activity, while d-alpha-tocotrienol manifests only about 30% of this activity. Since vitamin E is considered to be physiologically the most important lipid-soluble chain-breaking antioxidant of membranes, we studied alpha-tocotrienol as compared to alpha-tocopherol under conditions which are important for their antioxidant function. d-Alpha-tocotrienol possesses 40-60 times higher antioxidant activity against (Fe2+ + ascorbate)- and (Fe2+ + NADPH)-induced lipid peroxidation in rat liver microsomal membranes and 6.5 times better protection of cytochrome P-450 against oxidative damage than d-alpha-tocopherol. To clarify the mechanisms responsible for the much higher antioxidant potency of d-alpha-tocotrienol compared to d-alpha-tocopherol, ESR studies were performed of recycling efficiency of the chromanols from their chromanoxyl radicals. 1H-NMR measurements of lipid molecular mobility in liposomes containing chromanols, and fluorescence measurements which reveal the uniformity of distribution (clusterizations) of chromanols in the lipid bilayer. From the results, we concluded that this higher antioxidant potency of d-alpha-tocotrienol is due to the combined effects of three properties exhibited by d-alpha-tocotrienol as compared to d-alpha-tocopherol: (i) its higher recycling efficiency from chromanoxyl radicals, (ii) its more uniform distribution in membrane bilayer, and (iii) its stronger disordering of membrane lipids which makes interaction of chromanols with lipid radicals more efficient. The data presented show that there is a considerable discrepancy between the relative in vitro antioxidant activity of d-alpha-tocopherol and d-alpha-tocotrienol with the conventional bioassays of their vitamin activity.

Animals↗
PubMed1990

Antioxidant effects of ubiquinones in microsomes and mitochondria are mediated by tocopherol recycling.

Ubiquinones and tocopherols (vitamin E) are intrinsic lipid components which have a stabilizing function in many membranes attributed to their antioxidant activity. The antioxidant effects of tocopherols are due to direct radical scavenging. Although ubiquinones also exert antioxidant properties the specific molecular mechanisms of their antioxidant activity may be due to: (i) direct reaction with lipid radicals or (ii) interaction with chromanoxyl radicals resulting in regeneration of vitamin E. Lipid peroxidation results have now shown that tocopherols are much stronger membrane antioxidants than naturally occurring ubiquinols (ubiquinones). Thus direct radical scavenging effects of ubiquinols (ubiquinones) might be negligible in the presence of comparable or higher concentrations of tocopherols. In support of this our ESR findings show that ubiquinones synergistically enhance enzymic NADH- and NADPH-dependent recycling of tocopherols by electron transport in mitochondria and microsomes. If ubiquinols were direct radical scavengers their consumption would be expected. Further proving our conclusion HPLC measurements demonstrated that ubiquinone-dependent sparing of tocopherols was not accompanied by ubiquinone consumption.

Animals↗
PubMed1990

[The mechanisms of the antioxidant action of shielded phenols in biological membranes. The effects of 4-methyl-2,6-di-tert-butylphenol (ionol) and its derivatives].

According to Bulgarian-Soviet program "Biostab" we studied characteristics of different phenol compounds (ionol derivatives). The aim of the present study is to determine antiradical and antioxidant activity of a number of ionol derivatives in pure chemical systems and in different membrane fractions of a natural origin.

Animals↗
PubMed1990

Effect of subchronic treatment with some heavy metal salts on the activity of the drug metabolizing enzyme system in female rats.

In experiments on female albino rats the effect of 30-day treatment with salts of Co, Cd, Ni, Zn and Hg on the liver monooxygenase system was studied. It was found that CdCl2 and HgCl2 significantly decreased the activity of aniline hydroxylase whereas the activity of ethylmorphine-N-demethylase tended to remain almost constant and no significant changes were observed. The cytochrome P-450 level in Zn-treated female rats was decreased while the other metal salts did not change it. The cytochrome b5 levels were relatively stable and there were no significant differences between treated and untreated animals. Co, Cd and Hg decreased the NADPH-dependent lipid peroxidation whereas Ni and Zn did not change it. All metal salts caused no marked alterations in the female rat liver microsomal membrane fluidity.

Animals↗
PubMed1989

Mitochondria and microsomal membranes have a free radical reductase activity that prevents chromanoxyl radical accumulation.

Enzyme-dependent mechanisms which prevent accumulation of chromanoxyl radicals derived from the vitamin E analogue, 2,2,5,7,8-pentamethyl-6-hydroxycromane (PMC), were characterized in rat liver microsomal and mitochondrial membranes. The free radical oxidation product of PMC (chromanoxyl radical) was generated in membranes using either photochemical (uv light) or enzymatic (lipoxygenase and arachidonic acid) methods and detected by ESR. Substrates (NADH or NADPH) prevented accumulation of chromanoxyl radicals until the substrate was fully consumed. In microsomes, reduced glutathione increased the efficacy of NADPH in preventing the accumulation of the chromanoxyl radical, but was without effect in the absence of NADPH. Ascorbate also prevented accumulation of the chromanoxyl radical. It is concluded that rat liver microsomes and mitochondria have both enzymatic and non-enzymatic mechanisms for reducing chromanoxyl radicals.

Animals↗
PubMed1987

[Regulating and disturbing effects of alpha-tocopherol on lipid bilayers].

Using the high resolution 1H-NMR spectroscopy and spin-probes the influence of alpha-tocopherol on lipid bilayer microviscosity has been studied. It has been established that alpha-tocopherol shows the cholesterol-like action on the physical state of lipid bilayer: alpha-tocopherol increase microviscosity of unsaturated bilayers and decrease microviscosity of saturated bilayers. The character of alpha-tocopherol action is determined by the fatty acidic lipid composition but does not depend on the polar group structure of phospholipid molecule as cholesterol-like action of alpha-tocopherol is found itself in liposomes prepared both from phosphatidylcholine and phosphatidylethanolamine. Analog of alpha-tocopherol without phytol chain 2,2,5,7,8-penthamethyl-6-oxychroman does not show the cholesterol-like action as it is not able to disorder the saturated bilayers.

Electron Spin Resonance Spectroscopy↗