Biomedical subjects

K Magyar

Publications and source records attributed to K Magyar.

At least 19 recordsLinked to original sources

PubMed2004

Altered nitric oxide production in mouse brain after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridin or methamphetamine.

Several studies have demonstrated the involvement of reactive nitrogen and oxygen species (RNOS) in the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridin (MPTP) and methamphetamine (METH), so the contribution of altered nitric oxide synthase (NOS) enzyme function can be suspected. In this study, about 50% increase in nitric oxide (NO) production in the mouse striatum was found between 4 and 12 h after a single MPTP injection, allowing an increased peroxynitrite (ONOO-) formation in the target brain region. However, METH injection induced a rapid decrease of NO formation both in mouse striatum and hippocampus, reaching its minimum level at 2 h, and restored to the control value after 6 h in the striatum and 12 h in the hippocampus. The uncoupled function of NOS with increased superoxide (O2*-) production after METH injection is suggested.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2004

Pharmacological aspects of (-)-deprenyl.

Deprenyl, the selective irreversible inhibitor of monoamine oxidase-B (MAO-B), has been synthesised as a potential antidepressant, however, due to its dopamine potentiating capacity, became a registered drug in the treatment of Parkinson's disease. Deprenyl possesses a wide range of pharmacological activities; some of them are not related to its MAO-B inhibitory potency. Beside its dopamine potentiating effect, it renders protection against a number of dopaminergic, cholinergic and noradrenergic neurotoxins with a complex mechanism of action. By inducing antioxidant enzymes and decreasing the formation of reactive oxygen species, deprenyl is able to combat an oxidative challenge implicated as a common causative factor in neurodegenerative diseases. In a dose substantially lower than required for MAO-B inhibition (10(-9)-10(-13) M), deprenyl interferes with early apoptotic signalling events induced by various kinds of insults in cell cultures of neuroectodermal origin, thus protecting cells from apoptotic death. Deprenyl requires metabolic conversion to a hitherto unidentified metabolite to exert its antiapoptotic effect, which serves to protect the integrity of the mitochondrion by inducing transcriptional and translational changes. Pharmacokinetic and metabolism studies have revealed that deprenyl undergoes intensive first pass metabolism, and its major metabolites also possess pharmacological activities. The ratio of the parent compound and its metabolites reaching the systemic circulation and the brain are highly dependent on the routes of administration. Therefore, in the treatment of neurodegenerative diseases, reconsideration of the dosing schedule, by lowering the dose of deprenyl and choosing the most appropriate route of administration, would diminish undesired adverse effects, with unaltered neuroprotective potency.

Animals↗

PubMed2004

Semicarbazide-sensitive amine oxidase: current status and perspectives.

Semicarbazide-sensitive amine-oxidase (SSAO) is present in various human tissues and in plasma. Oxidative deamination of short-chain aliphatic amines is catalyzed by this enzyme to afford the corresponding aldehydes, ammonia and hydrogen peroxide. Methylamine and aminoacetone have been recognized to be physiological substrates for SSAO. There are several pathological states where increased serum SSAO activity have been found, such as diabetes mellitus, congestive heart failure, multiple types of cerebral infarction, uraemia, and hepatic cirrhosis. The role of SSAO in pathophysiology of diabetes has been most extensively investigated. The elevated formation of the potentially cytotoxic products of the enzyme may contribute to the endothelial injury of blood vessels, resulting in the early development of severe atherosclerosis; it may also contribute to the pathogenesis of diabetic angiopathy. It is now suggested that SSAO inhibitors may prevent the development of atherosclerosis and diabetic complications as well. Inhibitors can be conveniently subdivided into the main groups of hydrazine derivatives, arylalkylamines, propenyl- and propargylamines, oxazolidinones, and haloalkylamines. Of them, aryl(alkyl)hydrazines, and 3-halo-2-phenylallylamines are generally very strong SSAO inhibitors. Most of these inhibitors of SSAO have been originally developed for other purposes, or they are simple chemical reagents with highly reactive structural element(s); these compounds have not been able to fulfil all criteria of high potency, selectivity, and acceptable toxicity. New potent compounds with selectivity and low toxicity are needed, which may prove useful tools for understanding the roles and function of SSAO, or they may even be valuable substances for treatment of various diseases.

Amine Oxidase (Copper-Containing)↗

PubMed2003

Pro-apoptotic and anti-apoptotic molecules affecting pathways of signal transduction.

Selective inhibition of the "false" proliferative signals via targeting tyrosine kinases resulting in the induction of apoptosis by depletion of the "survival factors" is one of the most studied and widely accepted concepts of modern chemotherapy. We have synthesized a series of potent tyrosine kinase inhibitors and tested these compounds for apoptosis induction. Some of the tyrosine kinase inhibitors caused either apoptotic or cytoplasmic vacuolar cell death in various tumor cell cultures. The somatostatin analogue oligopeptide TT-232, which indirectly inhibits tyrosine kinases, exerted a dose-dependent apoptosis-inducing effect. The tumor growth-inhibitory effect of TT-232 and some tyrosine kinase inhibitors has also been proven by in vivo experiments, using human tumor xenografts. On the other hand, a dose-dependent pro- or anti-apoptotic activity of (-)-deprenyl has been shown in melanoma cell cultures, the lower doses inhibiting and the higher doses inducing apoptosis. Various metabolites of (-)-deprenyl are responsible for these actions. The effect of (-)-deprenyl is connected with depolarization of mitochondrial membranes. The kinase inhibitors act on the growth factor receptor signaling pathways (survival factor pathways) and initiate the caspase cascade. The key enzyme for the action of both pro-apoptotic and anti-apoptotic compounds is caspase 3.

Animals↗

PubMed2002

The influence of metabolism on the MAO-B inhibitory potency of selegiline.

(-)-Deprenyl (selegiline), a propargylamine derivative of methylamphetamine, is a potent, irreversible inhibitor of monoamine-oxidase type B (MAO-B). The MAO-B inhibitory effects of various doses (0.1-0.25-0.5 mg/kg) of (-)-deprenyl in rat brain and liver were compared, using either oral or subcutaneous drug administration. The intensity of the first pass metabolism of (-)-deprenyl was also estimated. The effect of pre-treatment with phenobarbitone (80 mg/kg i.p., daily for three days) or proadifen (SKF-525A, 50 mg/kg i.p., single dose) on the MAO-B inhibitory potency of (-)-deprenyl was also studied. The oral and subcutaneous administration of selegiline induced a significantly different degree of MAO-B enzyme inhibition in the rat brain, but not in the liver. The inhibitory potency of (-)-deprenyl on MAO-B activity was markedly influenced by pre-treatment of rats with an inducer (phenobarbitone), or an inhibitor (SKF-525A) of cytochrome P-450 mono-oxygenases in the liver. Our results suggest, that (-)-deprenyl is metabolised mainly in the liver by microsomal cytochrome P-450 dependent mono-oxygenases, and it has an intensive first-pass metabolism. The parent compound is responsible for the inhibition of MAO-B enzyme activity.

Animals↗

PubMed2001

The effect of low oral doses of (-)-deprenyl and its metabolites on DSP-4 toxicity.

Treatment with a single oral dose of (-)-deprenyl (selegiline) before DSP-4 administration could dose-dependently decrease the noradrenaline (NA) depleting effect of the toxin in mouse hippocampus. The maximum protective effect was achieved at as low oral dose as 0.25 mg/kg. Pre-treatment with the same doses of the main metabolites of (-)-deprenyl; (-)-amphetamine and (-)-methylamphetamine provided a weaker attenuation of DSP-4 induced NA depletion, than the parent compound. The selective noradrenergic toxin DSP-4, which depletes NA in nerve terminals originating from the locus coeruleus, is presumably metabolised by CYP-450 enzymes. Continuous administration of low, by themselves non-toxic doses of DSP-4 resulted in the cumulation of its NA depleting effect.

Administration, Oral↗

PubMed2001

Protective effect of 7-nitroindazole against DSP-4 induced noradrenaline depletion in mouse hippocampus.

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a selective noradrenaline (NA) uptake blocker, capable of inducing a long-lasting depletion of NA in some noradrenergic axon terminals originating from the locus coeruleus in rodents. Pretreatment with 7-nitroindazole, a fairly selective inhibitor of neuronal nitric oxide synthase in vivo, partially prevented DSP-4 induced NA depletion in mouse hippocampus measured seven days after the neurotoxic insult. Administration of L-arginine, the substrate of nitric oxide synthase, altered neither the NA depletion induced by DSP-4, nor the protective effect of 7-nitroindazole. Inhibition of nitric oxide synthesis by N(G)-nitro-L-arginine methyl ester did not attenuate the NA depleting effect of DSP-4. Thus, the contribution of neuronal nitric oxide synthase inhibition to the protective effect of 7-nitroindazole needs further studies. As 7-nitroindazole did not block NA uptake, this cannot play a part in the protective effect. The possible contribution of monoamine oxidase B enzyme inhibition by 7-nitroindazole to the protective effect is also discussed.

Animals↗

PubMed2001

Anti-apoptotic and apoptotic action of (-)-deprenyl and its metabolites.

The mode of cytoprotective action of the monoamine oxydase B inhibitor (-)-deprenyl was studied using A-2058 human melanoma cells in culture. Serum deprivation caused apoptosis of the cultured cells, which could be decreased by administration of 10(-9) - 10(-13)M (-)-deprenyl. The known metabolites of (-)-deprenyl, (-)-desmethyl-deprenyl, (-)- and (+)-methylamphetamine failed to exert the same effect. The anti-apoptotic activity of (-)-deprenyl was prevented by the simultaneous application of the microsomal drug-metabolizing enzyme inhibitor SKF-525A. These results show that (-)-deprenyl needs metabolic conversion in order to be anti-apoptotic, but the effective metabolite is still unknown. On the other hand, higher dose (10(-13)M) of (-)-deprenyl, (-)-desmethyl-deprenyl, (-)- and (+)-methylamphetamine induced apoptosis in the non-serum-deprived A-2058 cell culture. SKF-525A did not prevent the apoptosis-inducing effect of (-)-deprenyl, which means that no metabolic changes are needed for this activity. High dose (10(-3)M) of (-)-deprenyl induced very high Caspase 3 activity in non-serum-deprived A-2058 cell culture, low doses (10(-9) - 10(-3) M) of (-)-deprenyl maintained Caspase 3 activity on control level in case of serum-deprivation.

Adrenergic Agents↗

PubMed2000

Transdermal formulations of deprenyl: guinea pig and pig models.

The efficacy of many drugs relies on their presence at the site of action over a period of time. The retardation or programmed release capability of the conventional dosage forms like oral and parenteral are limited and toxic and undesired side-effects may occur after their applications. These problems may be solved using transdermal delivery systems. Transdermal systems are aimed for local, or systemic action. In the letter case controlling the rate of delivery or modulating the distribution in the organism. The selection of an adequate biological method of evaluating a new transdermal formulation is a critical point of the development. The in vitro methods can help in the characterization of the different formulas, but without an in vivo disposition study they cannot give relevant information about the expectable therapeutic behavior. We adapted and improved an in vivo test system for the evaluation of new transdermal particulate systems (patches) and liposomes containing deprenyl selegiline as active ingredient. The in vivo evaluation system consists of two steps: 1. Full biodisposition study on guinea pig, using isotope labeled selegiline. 2. Biodisposition studies on domestic pigs including dose, area, surface dependence and comparative bioavailability with traditional dosage forms and application moods. Specific examples of these studies and experimental technology are presented.

Administration, Cutaneous↗

PubMed2000

Inhibitor sensitivity of human serum and vascular semicarbazide-sensitive amine oxidases.

Recent data suggest that elevated serum semicarbazide-sensitive amine oxidase activity (SSAO) may cause endothelial injury. Formation of cytotoxic metabolites (especially formaldehyde) and increased oxidative stress might lead to initiation or progression of atherosclerosis. Effective and selective inhibitors of human SSAO might exert cytoprotective effect on endothelial cells. To compare the inhibitor sensitivity of human serum and vascular tissue SSAO enzyme, the inhibitory effect of semicarbazide and MDL 72974A was investigated. Serum and vascular SSAO activity has been determined using 14C-benzylamine as a substrate. The IC50 values of semicarbazide were estimated to be 5x10(-3) M and 5x10(-4) M for SSAO from human serum and saphenous vein, respectively. MDL 72974A amine oxidase inhibitor was more than thousand times more effective than semicarbazide. The IC50 values were 10(-7) M and 10(-8) M for SSAO from human serum and saphenous vein, respectively. This finding supports the hypothesis that soluble and membrane-bound vascular SSAO enzymes might have similar structure.

Allyl Compounds↗

PubMed2000

Apoptotic and antiapoptotic effect of (-)deprenyl and (-)-desmethyl-deprenyl on human cell lines.

The antiapoptotic effect of (-) deprenyl on human phaeochromocytoma cells after serum deprivation has been reported by earlier. Two melanoma (M-1 and HT-2058) cell lines were used in our experiments. Serum deprivation for five days resulted in excessive number of apoptosis in the cell cultures. Very low doses of (-)-deprenyl (10(-7)-10(-13) mol) caused an approximately 2 days delay in the onset of apoptosis. At the same time, +deprenyl was ineffective. In further experiments (-)-deprenyl and (-)desmethyl-deprenyl was administered in higher doses (10(-2), 10(-3) and 10(-4) mol) to A-2058 melanoma and HT-1080 fibrosarcoma cells in culture. In these experiments no serum deprivation was applied and the treatment was started 24 hours after plating. Total eradication of the A-2058 cells was caused by 10(-2) mol (-)-deprenyl and (-)-desmethyl-deprenyl. The type of cell death appeared to be apoptosis. Sixty percent apoptotic ratio was seen 24 hours and 72 hours after 10(-3) mol (-)-desmethyl-deprenyl treteatment. The same dose of (-)-deprenyl caused 50% apoptosis an 72 h. Only (-)-desmethyl-deprenyl induced apoptosis (20%) at 24 hours, in the dose of 10(-4) mol. Interestingly (-)-deprenyl treatment resulted in 60% apoptosis.

Amphetamines↗

PubMed2000

Effect of MAO inhibitors on the high-affinity reuptake of biogenic amines in rat subcortical regions.

The noradrenaline (NA), dopamine (DA) and serotonin (5HT) reuptake inhibitory potency of deprenyl, the highly selective and irreversible inhibitor of MAO-B, methamphetamine enantiomers, and some other MAO inhibitors (clorgyline, J-508, J-511, J-512, J-516, LK-63, U-1424, 2-HxMP) was compared. In vitro hypothalamic NA reuptake was inhibited by (+)-, and (-)-methamphetamine, (+)- J-508 and (+)-deprenyl (IC50: 0.35, 3.5, 17.0 and 17.8 mumol/l, respectively), and U-1424, J-512, J-516, LK-63 and 2-Hx-MP showed IC50 > 1000 mumol/l. Striatal DA reuptake was inhibited by (+)-, and (-)-methamphetamine, (+)-, and (-)-deprenyl and clorgyline with IC50 of 0.6, 42.0, 24.0, 98.6 and 27.0 mumol/l, respectively, however the other compounds were ineffective. Hippocampal 5HT reuptake was slightly inhibited by clorgyline (IC50 205.0 mumol/l), while the other MAO-inhibitors were devoid of potency. Data suggest that potency and selectivity of MAO inhibition and reuptake inhibition are independent features of the compounds, and metabolism of deprenyl results in increased noradrenaline and dopamine reuptake inhibition.

Animals↗

PubMed1999

Elevated serum semicarbazide-sensitive amine oxidase activity in non-insulin-dependent diabetes mellitus: correlation with body mass index and serum triglyceride.

Previous clinical studies reported elevated semicarbazide-sensitive amine oxidase (SSAO) activity in insulin-dependent diabetes mellitus (IDDM), but there are not sufficient data about SSAO in non-insulin-dependent diabetes mellitus (NIDDM). The present study was conducted to investigate serum SSAO activity in NIDDM patients compared with nondiabetic and IDDM patients. Serum SSAO activity in 61 patients with diabetes (n = 34 NIDDM and n = 27 IDDM) and 36 controls was determined using 14C-benzylamine as a substrate. NIDDM and IDDM patients exhibited higher SSAO activity compared with controls ([mean +/- SD] NIDDM, 164.60+/-69.43 pmol/mg protein/h, P<.0001; IDDM, 143.91+/-72.45 pmol/mg protein/h, P<.002; control, 91.46+/-28.11 pmol/mg protein/h). There was a significant positive correlation between serum SSAO activity and the body mass index (BMI), body weight, hemoglobin A1c (HbA1c), fasting plasma glucose, and triglycerides. Within the control group, SSAO correlated with total cholesterol levels. The progression and severity of diabetic complications such as angiopathy may be exacerbated by cytotoxic metabolites (e.g., formaldehyde and hydrogen peroxide) formed by SSAO. These results reveal the possibility that elevated serum SSAO activity in association with obesity and hyperlipidemia may be a cardiovascular risk factor in diabetes mellitus.

Adult↗

PubMed1999

Zootechnical and genetic aspects of a prolific merino program.

In a Prolific Merino nucleus herd of 200 ewes the ovulation rate (OR) test results obtained in 169 animals between 1988 and 1993 were compared with those of 113 ewes from the same herd in 1996. Whereas earlier the ratio of individuals showing an OR > or = 4 was only 32%, that of the group checked in 1996 was 59%. This increase could be attributed to 40 ewes, both of whose parents had proven to be homozygous carriers of the prolific gene. To develop the Prolific Merino breed, 21 Booroola Merino rams were imported from New Zealand, and mostly their frozen semen was used. Of these rams, one was not a prolific gene carrier, 8 were homozygous carriers, 10 were heterozygous carriers and two had not been identified yet. Of the 36 home-bred rams, 9 proved to be homozygous by parents, 11 heterozygous, 8 homozygous, one proved to be a non-carrier, and 7 rams and their frozen semen were to be progeny tested. Six thousand doses of frozen semen from a total of 33 animals (16 imported rams and their 17 home-bred offspring) are stored in plastic straws. Sixty-three % of this is semen reserve from rams of the FecBFecB genotype, belonging to 10 ram lines. The remaining 37% is gene reserve intended for creating homozygous ram lines. Only one ram (no. 3244) was bought for the nucleus herd, the other ram lines were introduced into the herd by assortative mating, using intrauterine insemination. The average conception rate found after 472 intrauterine inseminations was 53% with large (occasionally 10-100%) individual ram differences.

Animals↗

PubMed1999

Analysis of deprenyl metabolites in the rat brain using HPLC-ES-MS.

Methylamphetamine and amphetamine, the two major metabolites of deprenyl in the rat brain were analyzed using HPLC method combined with electrospray-mass spectrometer. (-)-Deprenyl and (+)-deprenyl were orally administered to rats either in a single dose of 10 mg/kg, or three times a week for three weeks. The metabolites were determined in four different parts of the rat brain, such as in the frontal cortex, corpus striatum, hippocampus, and hypophysis. The ratio of methylamphetamine to amphetamine was also compared after (-)-deprenyl and (+)-deprenyl treatments.

Amphetamine↗

PubMed1999

[Pre- and postsynaptic action of the ATP-dependent K+-channel-(K+ATP)-opener pinacidil in rabbit pulmonary artery].

Low frequency (2 Hz) of electrical depolarisation induced [3H]noradrenaline ([3H]NA) release has been measured from the isolated main pulmonary artery of the rabbit in the presence of uptake blockers (cocaine, 3x10(-5)M and corticosterone, 5x10(-5)M), with parallel measurements of post-junctional contractile responses. The K+ATP-channel opener pinacidil (10(-6)-10(-4)M), slightly potentiated the nerve-evoked release of [3H]NA which failed to show close concentration-dependency. Large concentration of pinacidil (10(-4)M) increased the ratio of [3H]NA release from 0.99 +/- 0.02 to 1.28 +/- 0.05 (P < 0.0005). On the other hand, pinacidil inhibited the nerve-evoked contractions in a concentration-dependent manner. 10(-4)M caused nearly 70% inhibition of contractile response. The pre- and post-junctional effects of pinacidil were studied under the following experimental conditions: 1) exogenously applied 1-NA; 2) excess K+; 3) 'L-type' Ca(2+)-channel activation (BAY K 8644); K(+)-channel inhibition (4-AP); and 5) Na(+)-pump inhibition/reactivation. Pinacidil (10(-4)M) retained its marginal NA-release stimulatory effect in all cases. However, pinacidil inhibited the contraction of smooth muscle, although to a different extent, in all of the experimental conditions used in our study.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1999

Neuroprotective and neuronal rescue effects of selegiline: review.

The effect of selegiline [(-)-deprenyl] cannot be considered as a simple, selective inhibitor of MAO-B. Pretreatment with the drug prevented the effect of specific neurotoxins like MPTP, 6-OH-dopamine, DSP-4 and AF64A. Selegiline pretreatment prevented the depletion of noradrenaline (NA) induced by DSP-4 in the rat hippocampus. This can be due to the uptake inhibitory effect of selegiline and mainly to its metabolite methylamphetamine (MA), which is more potent inhibitor of the re-uptake than the parent compound. SKF-525A pretreatment diminished the protective effect of selegiline against DSP-4, while phenobarbital pretreatment decreased its MAO-B inhibitory potency. Selegiline in low oral doses also prevented the effect of DSP-4 due to its intensive "first pass" metabolism. Selegiline treatment can rescue damaged neurones. It inhibited the apoptosis in M-1 human melanoma cells in a rather low concentration (10(-13)M). The mode of action of the drug regarding the inhibition of apoptosis is not known.

Animals↗

PubMed1999

Metabolic transformation of deprenyl enantiomers in rats.

The optical isomers of deprenyl have different pharmacological activities and potency. Selegiline, an (-)-isomer, is the more potent monoamine oxidase B enzyme inhibitor, and this substance is used in the therapy of Parkinson's disease. The neuroprotective and neuronal rescue effects of deprenyl, as well as the psychostimulant action of its metabolites, methamphetamine and amphetamine are also different for the enantiomers. In this study the biotransformation of deprenyl enantiomers was compared. Stereoselective dealkylation of both optical isomers was found as major metabolic alteration. The difference in the ratio of the formed metabolites suggests the existence of preferred metabolic pathways for the enantiomers.

Amphetamine↗