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I Zs -Nagy

Publications and source records attributed to I Zs -Nagy.

At least 19 recordsLinked to original sources
PubMed2001

Comparison of the lateral diffusion coefficient of hepatocyte plasma membrane proteins in three strains of sensescence accelerated mouse (SAM).

The lateral diffusion coefficients of proteins (D(p)) were measured in hepatocyte plasma membrane in freshly prepared liver smears by means of the fluorescence recovery after photobleaching (FRAP) method. D(p) was measured after development of peroxide-induced autofluorescence (PIAF) in a total of 115 senescence accelerated mice (SAM), distributed in three strains, at least five age-groups in each, as follows: (i) SAMR1TA (25 males and 22 females), medium life span (MLS) in months, under specific pathogen free (SPF) conditions, MLS(spf) 20.1 and 20.0, respectively, while under conventional conditions, MLS(Deltapf)=18.9 in average for both sexes; (ii) SAMP6/Ta (18 males and 17 females), MLS(spf)=17.1 and 15.3, respectively, and MLS(cc)=8.1 for both sexes; (iii) SAMP6/Ta (17 males and 16 females), MLS(spf)=15.6 and 14.7, respectively, and MLS(cc)=10.0 for both sexes. A highly significant negative linear age-correlation of D(p) (R=0.975 or higher) was found in each strain, being roughly proportional with the MLS(cc) values. Since the studied mice kept under SPF conditions survived longer, than under conventional conditions, the actual age-dependent decay rates of D(p) values did not differ significantly in two pairs of comparisons (female R1/P6 and female R1/P8), whereas they did in all other possible pairs, including also the normal C57BL/6 mice. The main conclusion can be drawn that the D(p) of hepatocyte membranes is a good biomarker of aging and survival also in SAM, as in all other inbred and outbred rodents, studied so far.

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PubMed2001

Editorial.

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PubMed2001

The involvement of hydroxyl free radicals in differentiation of the PC-12 rat pheochromocytoma cell line.

These experiments tested the differentiation properties of the PC-12 cell line under conditions of in vitro generation of OH&z.rad; free radicals by Fenton reaction. This involves the simultaneous addition of the following reactants: ADP-Fe(2+)-complex (0.1 mM for iron) and H(2)O(2) (0.025 mM), final concentrations. Superoxide dismutase activity, the increase of which is considered as a marker of differentiation, catalase and glutathione peroxidase enzyme activities were investigated, which all displayed significant increases after single and repeated interventions with hydroxyl free radicals, while the cell number remained nearly at the starting-value. It is known that the differentiation takes place when the cell number has reached a plateau. These data, therefore, suggest that hydroxyl free radicals can induce in vitro cell differentiation, and that they play a more complex role in cell physiology than simply causing oxidative damages. It is interesting that the cells can maintain high levels of these enzyme activities for a relatively long time (2 or 4 days) after a very short flux of hydroxyl free radicals.

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PubMed2001

Experimental gerontology in Hungary.

Gerontological research has some past and sporadically also some highlights in Hungary, but its present state can be easily deduced from the following data. During the last 12 years and more, well over 10,000 Hungarian scientific papers have been published in well-recognized national or international journals. Altogether approximately 1% of them have been classified as gerontological publications from Hungary. This low figure shows that gerontology has low priority and--unfortunately low support--in Hungary. This statement does not intend to downgrade Hungarian gerontologists, however points out that the Hungarian trends are not far from those of European or world wide interest in aging. Despite the recognition that we have to accept the inevitable fact that industrial societies will have (they already have) an aging population with all the social and medical problems arising, the focus of interest is wide from this significant and interesting (sub)population, which is neglected (sometimes even despised); yet everybody is absolutely eager to join this club. The average of the Hungarian research achievements and publication activities are among the better European achievements. There are some highlights and new trends even initiated by some outstanding Hungarian scientists, yet the overall weight of gerontology research is still an orphan in the Hungarian scientific life. We deal in this short and far from complete summary almost exclusively with experimental gerontology. We have to apologize if we have not included everybody, who also contributed even significantly to this field because the time for the preparation of this overview was short.

Aging↗
PubMedDate not supplied

Effects of centrophenoxine on body composition and some biochemical parameters of demented elderly people as revealed in a double-blind clinical trial.

A double-blind clinical trial was performed on 50 persons (25 men, 25 women, average age 77 years) suffering from dementias of medium level (DSM III, Category 1, ICD No. 299). All subjects were residents in an old age home. The patients were treated first for 2 weeks by placebo tablets. During this period, body composition parameters were determined and these data served as controls. This was then followed by an 8-week-long treatment with the nootropic drug, centrophenoxine (CPH), 2 g/day distributed in 2x2 tablets of Helfergin(500) (Promonta, Hamburg, F.R.G.), or placebo tablets of identical size. After 8 weeks the laboratory tests were repeated again. The randomization code for verum or placebo treatment was revealed only after completing the trial. Four dropouts occurred during the treatment period. The total body water, extracellular water volume and exchangable Na(+) were determined by means of radioisotope methods. Plasma volume (PV) was measured by indocyanine-green dilution test. Body weights were also recorded. From the above data further parameters could be calculated. Serum lipid data as well as several hormone levels were also checked in the blood samples. The main results were better performance in psychometric tests (Pék et al., 1989) and a significant increase of the average intracellular water content (2.2-2.5% by weight) in the verum-treated group. The rehydration of the intracellular mass due to CPH treatment is consistent with the OH(*.) free radical scavenger properties of CPH and the predictions of the membrane hypothesis of aging.

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PubMedDate not supplied

Chemistry, toxicology, pharmacology and pharmacokinetics of idebenone: a review.

The name idebenone (CV-2619) was given to a synthetic compound the chemical structure of which is 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (commercial name in Japan: Avan). Although it is insoluble in water, suspensions of it can be applied and are absorbed relatively well from the intestine. Its acute toxicity is very low, and is well tolerated also in subacute and chronic treatments. It displayed no immunogenic or mutagenic side effects in the models studied so far. Pharmacological studies of idebenone revealed that (i) it acts as a free radical scavenger and protects the mitochondrial membrane against lipid peroxidation; (ii) it prevents platelet aggregation; (iii) it improves vascular disorders due to strokes or experimental cerebral ischemia; (iv) it recovers the cholinergic and monoaminergic changes in the ischemic brain; (v) it improves overall brain function (including memory, also) in various animal models. Pharmacokinetic studies have confirmed that it reaches the brain cells even after per os administration. The main conclusion from the experimental data was that idebenone may be of beneficial effect for the neurological disorders related to cerebral ischemia even in humans: the results obtained so far in human clinical trials confirmed the validity of this expectation for cases of human cerebrovascular disease.

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In vitro studies on the OH* and O2(-*) free radical scavenger properties of idebenone in chemical systems.

OH(*) free radicals were generated by Fenton reaction in the presence of bovine serum albumin (BSA). The decreasing water-solubility of BSA with increasing Fe(2+) concentrations of the system is a sensitive indicator of the cross-linking effects of the OH(*) free radicals. Idebenone (oxidized form) was solubilized for this experiment in DMSO and added to the system in final concentrations of 0.01 or 0.1%. Neither of these concentrations displayed any protective effect against the insolubilization of BSA. Therefore, oxidized idebenone has to be considered as a substance which reacts with OH(*) free radicals slower than the BSA itself, i.e., its oxidized form is not an efficient scavenger of this type of free radicals under the given circumstances. The ability of idebenone to scavenge superoxide radicals was tested in ( [Formula: see text] ) the pyrogallol system; and (ii) the xanthine-xanthine oxidase-nitro blue tetrazolium (XXO-NBT) system. Idebenone did not show any O(2)(-*) radical scavenging ability as revealed by these two in vitro methods, in the concentration ranges studied (up to 75 or 220 microg/ml, respectively). On the contrary, an increasing O(2)(-*) radical generation was observed with increasing concentrations of the drug in both test systems used. The possible biological significance of these observations is discussed in the light of other results like ESR spin trapping and measurements of superoxide dismutase (SOD) activity in various tissues.

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PubMedDate not supplied

Superoxide radical scavenging activity of idebenone in vitro studied by ESR spin trapping method and direct ESR measurement at liquid nitrogen temperature.

The radical scavenging activity of oxidized and reduced idebenone (ID-O and ID-H, respectively) against superoxide radical (O2(-*) was studied in vitro using two methods: (1) O2(-*) radicals were generated enzymatically in a hypoxanthine (HPX)-xanthine oxidase (XOD) system and detected by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) spin trapping. Superoxide dismutase and other scavengers added to this system competed to various extents with DMPO to trap O2(-*) radicals, resulting in a decrease of the ESR signal intensity of the DMPO-OOH spin adduct. ID-O reacted about 12-fold quicker (k = 4.48 x 10(4) M(-1)s(-1)) with the O2(-*) radicals than ID-H (k = 3.62 x 10(3) M(-1)s(-1)) x (2) O2(-*) radicals were generated chemically in potassium superoxide (KO2)-crown ether system. Quinoid compounds reacted with the O2(-*)radicals to form semiquinone radicals that could be observed by ESR. At liquid nitrogen temperature (-196 degrees C), the ESR signal of O2(-*) radicals could be observed directly, thus allowing us to estimate the scavenging activity of ID-O and ID-H. These experiments also revealed that ID-O possesses an O2(-*) radical scavenging activity, whereas ID-H reacts quantitatively much slower. Analyzing various quinone compounds, it has been established that the O2(-*) radical scavenging process is a reversible, most probably oscillating, monovalent electron transfer from superoxide to the quinone, and that the O2(-*) radical scavenging activity depends on the redox potential, i.e., on the actual state of oxidation of the quinones.

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ESR spin trapping studies on the OH* free radical reactions of idebenone.

Experiments have been performed using oxidized (ID-O) and reduced (ID-H) idebenone in various spin trapping systems. The following results were obtained. (1) ID-O does not have any detectable scavenger effect on the OH* free radicals when they are generated by means of Fenton reaction and trapped using DMPO, PBN or 4-POBN. (2) ID-H represents a serious competition for all spin traps used in capturing OH* free radicals. The mechanism of this competition is, however, not a direct reaction, but it is based on the rather quick autoxidation of the dissolved ID-H generating O2(-*) radicals. They interact with the OH* radicals (or with the OH-spin adducts) by means of electron donation to them. This statement has been proven by showing (i) that O2* radicals generated during the autoxidation of ID-H can directly be trapped on DMPO; (ii) the effect of ID-H on the OH* free radicals is abolished if SOD is added to the system; (iii) the O2(-*) radicals generated by ID-H autoxidation reduce directly the OH-spin adducts on various kinds of nitroxide type spin traps (e.g. TEMPO, TMPN). (3) The rate of autoxidation of ID-H in solution is about an order of magnitude faster than that of ubiquinone. Similar differences could be observed in the rate of reduction of the oxidized forms of both compounds by Na-borohydride. The results fully explain the in vitro protective effect of ID-H against lipid peroxidation of artificial membranes.

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PubMedDate not supplied

Effects of idebenone on the composition of brain synaptosomal membranes of rats.

Male and female CFY rats of 21 months of age were treated per os by 50 mg idebenone per kg body weight/day for 5 weeks while the controls received only the solvent. Synaptosomal fractions of the brain cortex were prepared and tested as follows: (1) Labeling by 1,6-diphenyl-1,3,5-hexatriene (DPH) and the fluorescence anisotropy (r) of this label was measured at various optical densities. The average values of r extrapolated to zero optical density were 0.1831 +/- 0.0025 in the control group and 0.1854 +/- 0.0019 in the idebenone-treated animals; the difference is statistically not significant. (2) Labeling with 3 different spin labels (5-NS, N-oxyl-4', 4'-dimethyloxazolidine derivative of stearic acid with the doxyl groups in C-5; 16-NS, the same derivative of stearic acid with the doxyl groups in C-16 position; and MAL-SL, 3-maleimido-2,2,5,5-tetramethyl-1-pyrrolidinyloxy). Routine ESR spectroscopy was applied to characterize the molecular motion of these labels in their microenvironment. These spin labels did not display any significant change in their environment under the influence of idebenone treatment. (3) Protein contents of the samples were measured and samples of synaptosomes containing 3.5 mg protein were dissolved in 1% Na(Dod)SO4 + 1% beta-mercaptoethanol and boiled for 2 min, then elaborated by gel filtration chromatography on a column of sepharose 2B. The elution fluid was collected in separate fractions of 1 ml volume and their protein content was estimated by measuring the absorbance at 280 nm. Distribution histogram of the protein fractions revealed no difference between the placebo- and verum-treated animals. These studies demonstrate that in vivo application of idebenone does not alter the composition of synaptosomal membranes.

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The effect of idebenone on the lateral mobility of proteins in hepatocyte plasma membrane of old rats as revealed by fluorescence recovery after photobleaching (FRAP) technique using an endogenous label.

The average lateral diffusion constant of proteins (D) in the cell membrane of hepatocytes has been measured in liver smears by fluorescence recovery after photobleaching (FRAP) based on the so-called peroxide-induced autofluorescence (PIAF) deriving from the oxidation of riboflavin bound to membrane proteins. It has been shown before that D displays a significant negative linear age-correlation. The in vivo effect of idebenone was tested on this parameter. Old (23.7 months at killing) male Fischer 344 rats received 50 mg of the drug per kg body weight per os through gastric tube, suspended in 5% gum arabic solution (Verum I group) or the same dose and form of idebenone completed by 80 mg centrophenoxine per kg body weight (Verum II group) for 35 days. D was measured on a double blind basis in hepatocyte plasma membrane of the Verum or Placebo (5% gum arabic, only) groups. A significant increase of D (29.6%) was induced by idebenone in the Verum I group; nevertheless, even the Placebo group displayed a moderate, but statistically significant increase of D (10.7%). The Verum II group showed a total of 39.6% increase in the value of D. The loss of body weight being characteristic for these animals at the age of around 2 years was between 0.87 and 1.06 g/day, whereas in other experiments higher values (1.77 g/day) were observed in the controls.

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The effect of idebenone on the passive K+ and Rb+ permeability of the brain cell membranes of CFY rats as revealed by the Rb+-discrimination ratio.

Rubidium (Rb(+)) uptake and release of brain cortical neurons of adult (12-15 month old), normal, female CFY rats were studied in placebo- and idebenone-treated animals. Treatment period was up to 5 weeks, with 50 mg/kg bw/day idebenone (oxidized form) suspended in 5% gum arabic (verum-group), or only with the latter solvent (placebo-group). Rb(+) can replace up to 60% of the intracellular K(+), and can be used as a tracer of the K(+) movement across the cell membrane. Loading with RbCI was performed from the 3rd week of the idebenone treatment by daily intraperitoneal injections of a dose of 300 mg/kg bw, for 14 days. During the subsequent Rb(+)-release period, the so-called Rb(+)/K(+) discrimination ratio (DR) (Relman et al., 1957, J. Clin. Invest., 36, 1249) was determined on the 3rd and 8th days. Rb(+) and K(+) contents were measured by means of bulk specimen X-ray microanalysis in the intracellular water of brain cells and by atomic absorption spectrophotometry in the serum, in 3-4 animals per group, whereas these concentrations in the cerebrospinal fluid were calculated on the basis of known serum/liquor distribution factors. Normal aging causes a marked increase of DR in brain and liver cells. The values of DR obtained in both placebo and verum groups were identical with those of the age-matched, completely untreated controls. It is important to stress that the subacute idebenone treatment did not cause any deterioration of this parameter, i.e., under the given conditions idebenone does not affect the cell membrane passive Rb(+) and K(+) permeability characteristics in the neurons of adult, normal, female CFY rats.

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Electron microscopic morphometric studies on the effects of idebenone on the synaptic remodelling activity in the hippocampus and cerebellum in normal old as well as in vitamin E-deficient adult rats.

Electron microscopic morphometric investigation has been carried out on the synaptic junctions of the hippocampal dentate gyri and cerebellar glomeruli of normal, old female Wistar rats (29 months of age), and vitamin E-deficient, female adult rats (11 months of age) of the same strain. The vitamin E-deficient diet was maintained from the age of 1 month for the subsequent 10-month period. Both the normal old and the vitamin E-deficient rats were treated with a daily dose of 50 mg oxidized idebenone/kg body w/day or with its solvent (5% gum arabic) through a gastric tube during the last month before killing them. The following morphometric parameters were evaluated in the hippocampal dentate gyrus and cerebellar glomerulus: the average length of the synapses (L) the surface density (S(v)) and the numerical density (N(v)) of the synaptic contact zones. Although the idebenone treatment caused a tendency to improve these parameters in both brain compartments studied, these improvements did not reach statistical significance in the cerebellum, but did so in the case of hippocampal N(v). Vitamin E deprivation caused the usual, known alterations of the synaptic parameters. Idebenone treatment during the last month of this experiment compensated the decrease of S(v) in both the hippocampus and the cerebellum; however, its protective effect was significant only in the case of hippocampus. Idebenone effect manifests itself in the increase of L, contributing mainly to the increase of S(v), since N(v) remained practically invariate. Placebo treatments did not result in any significant alterations in the vitamin E-deficient group.

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Effects of idebenone on the intracellular water and dry mass content as well as of the intracellular monovalent ion concentrations of brain cortical cells of SHRsp rats as revealed by X-ray microanalysis.

The cerebral cortex of ten male SHRsp rats kept in conventional housing conditions were studied. Starting from the age of 3 months, five animals received placebo (5% gum arabic solution) and five other rats received 50 mg/kg idebenone suspended in the gum arabic, through a gastric tube for 4 weeks (except Sundays). During the last 2 weeks of treatment, 0.9% NaCl was added to the drinking water. Several completely untreated SHRsp rats of various ages were also involved in these studies. Blood pressure was measured weekly on the tail by means of an appropriate instrument. Serious hypertension was observed already by the end of the second week of treatment, displaying values of 250-260 mm Hg and increased further by about 20 mm Hg during the last 2 weeks of treatment. Intracellular water, dry mass and monovalent electrolyte concentrations were measured by means of a bulk specimen X-ray microanalytic method. The brain cells contained 77+/-1% water and 23% dry mass by weight in both placebo and verum-treated groups. The intracellular Na(+) content of all the male SHRsp rats was found to be significantly higher (180-200%) in the brain cells, whereas K(+) content increased only moderately, when expressed as percent of the intracellular dry mass. Idebenone treatment, however, lowered the intracellular Na(+) content of the brain cells to a significant extent (about 20%), i.e., it improved the Na(+) tolerance of the SHRsp rats, but did not alter the blood pressure.

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The effects of idebenone on the superoxide dismutase, catalase and glutathione peroxidase activities in liver and brain homogenates, as well as in brain synaptosomal and mitochondrial fractions.

The cerebral cortex and liver of 20 female CFY rats of 21 months of age (at killing), kept in conventional housing conditions, were studied. Ten animals received placebo (5% gum arabic solution) and 10 other rats received 50 mg/kg body weight/day idebenone suspended in the gum arabic, through a gastric tube for 5 weeks (except Sundays). Liver and brain homogenates were obtained by homogenization of tissue pieces (10 mg/ml) in 0.32 M sucrose solution. Synaptosomal and mitochondrial fractions of the brain cortex were prepared by using established methods of density gradient centrifugation, pooling together the brains of two animals for each experiment. Protein contents of the samples were measured by means of a modified folin-phenol method. Superoxide dismutase (SOD), catalase (CA) and glutathione peroxidase (GP) activities were measured by using established biochemical methods. The activities were compared in the placebo and verum groups on a protein weight basis. The SOD activity increased slightly (but not significantly) in the total brain homogenate, whereas both the mitochondrial and synaptosomal fractions of the cortex displayed significant increases of this enzyme activity (28.5 and 16.3% respectively). SOD and CA activities decreased in the liver homogenate and all other parameters remained invariate both in the brain and its subfractions, except CA in the synaptosomal fraction where a slight decrease occurred (-15.6%).

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The effects of idebenone on DNA and RNA contents as well as synthesis rates of total and poly(A)+ RNA in brain of normal, old C57BL/6J mice and in experimental partial cerebral ischemia of rats.

Effects of idebenone on RNA and DNA contents as well as on synthesis rates of total and poly(A)(+) RNA in the brain were measured in two animal models: (1) Normal young and old, male C57BL/6J mice (6 and 32 months). Idebenone suspended in 5% gum arabic was applied in 50 mg/kg/day dose to old mice for 1 month through a gastric tube. (2) Adult female CFY rats (14-18 months) in which experimental partial cerebral ischemia was induced by bilateral common carotid artery occlusion. Idebenone was administered intraperitoneally in two dose (10mg/kg and 100 mg/kg body weight) 30 min before the interruption of carotid blood flow. DNA content remained invariate during aging in the brain; idebenone treatment did not exert any influence on this parameter. RNA content as well as total and poly(A)(+) RNA synthesis rates, which were measured by incorporation of tritiated uridine into RNA, decreased significantly with age in brain. Idebenone treatment did not cause any essential change of the metabolism of RNA under the given conditions. The RNA and DNA contents of brain were influenced neither by experimental partial cerebral ischemia nor by treatment with idebenone during the ischemia. Partial cerebral ischemia decreased the rate of total and poly(A)(+) RNA synthesis in the brain about 15-45% depending on the methods and basis of expression. This decline could totally be prevented by intraperitoneal application of 10 mg/kg idebenone 30 min before the onset of the partial ischemia. The dose of 100 mg/kg idebenone also elevated the rate of RNA synthesis; however, this increase remained statistically insignificant.

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The horizons of an interdisciplinary synthesis in experimental gerontology.

This review summarizes the main points of an interdisciplinary, theoretically established approach to the problem of cell senescence, called membrane hypothesis of aging (MHA). The main knowledge and some new suggestions regarding the damaging and sometimes useful roles of the oxygen free radicals is outlined. The most important experimental results are listed, which harmonize with the MHA. It is emphasized that MHA is not an alternative to the other aging hypotheses but represents a synthesis of most of them. It is pointed out that the new drug design based on the MHA resulted in a useful new molecule which is able to improve the key cell parameters deteriorated by advancing age. The necessity of a closer international cooperation is emphasized, in order to achieve a breakthrough in experimental gerontology within this century.

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