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Biomedical subjects

A Lajtha

Publications and source records attributed to A Lajtha.

At least 199 records · Page 11Linked to original sources
PubMed1985

An opiate receptor-associated aminopeptidase that degrades enkephalins.

During the purification of opiate receptor by affinity chromatography on wheat germ agglutinin-agarose, an aminopeptidase is coeluted with the receptor. Virtually all of both the enzyme and the receptor is retained on the hydroxylapatite column. The aminopeptidase functions optimally at neutral pH and is activated by Mn2+. The enzyme is sensitive to dithiothreitol, is inhibited by amastatin and bestatin, and is insensitive to puromycin. The enzyme seems to be linked to the receptor, since its activity is enhanced by D-Ala2-Met-enkephalinamide or naltrexone. The properties of this aminopeptidase indicate that it is distinct from neutral arylamidase, leucine-aminopeptidase, aminopeptidases A and B, brain acidic aminopeptidase, and the membrane aminoenkephalinase that we purified recently (4).

Aminopeptidases↗
PubMed1985

Protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity by the antioxidant ascorbic acid.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 2 X 8 mg/kg retro-orbital) to BALB/cBy mice reduced [3H]mazindol binding to striatal membranes by 50%. Reactive oxygen derivatives have been suggested to be involved in MPTP neurotoxicity; therefore we examined the effects of ascorbic acid (an antioxidant). Ascorbic acid (100 mg/kg) given 20 min prior to MPTP administration appreciably prevented the reduction of [3H]mazindol binding. The involvement of oxidative processes in the mechanism of MPTP neurotoxicity may suggest a relationship to the etiology of Parkinson's disease, and the possible benefit of treatment with ascorbic acid.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Locomotor effects of cocaine, cocaine congeners, and local anesthetics in mice.

Spontaneous locomotor activity of mice was stimulated by IP administration of cocaine and its closely related phenyltropane analogs. In contrast, locomotion was inhibited by IP administration of cocaine congeners such as norcocaine, (+)-pseudococaine, and tropacocaine, and of isomers of phenyltropane analogs. Also inhibitory were the local anesthetics procaine, tetracaine, benzocaine, lidocaine, and prilocaine. The locomotor inhibition induced by IP norcocaine or tetracaine could be reversed by subsequent treatment with cocaine. Both cocaine and norcocaine were centrally stimulatory when injected intracerebroventricularly. The rank order of potencies of cocaine congeners and local anesthetics in depressing locomotion was similar to that of their potencies in interacting with sodium channels. From these results we infer that the locomotor depression induced by systemic administration of cocaine congeners results from a local anesthetic action involving inhibition of the ion conductance of sodium channels.

Anesthetics, Local↗
PubMed1985

Action of brain cathepsin B, cathepsin D, and high-molecular-weight aspartic proteinase on angiotensins I and II.

The action of three previously isolated electrophoretically homogeneous brain proteinases--cathepsin B (EC 3.4.22.1), cathepsin D (EC 3.4.23.5), and high-molecular-weight aspartic proteinase (Mr = 90K; EC 3.4.23.-)--on human angiotensins I and II has been investigated. The products of enzymatic hydrolysis have been identified by thin-layer chromatography on Silufol plates using authentic standards and by N-terminal amino acid residue analysis using a dansyl chloride method. Cathepsin D and high-molecular-weight aspartic proteinase did not split angiotensin I or angiotensin II. Cathepsin B hydrolyzed angiotensin I via a dipeptidyl carboxypeptidase mechanism removing His-Leu to form angiotensin II, and it degraded angiotensin II as an endopeptidase at the Val3-Tyr4 bond. Cathepsin B did not split off His-Leu from Z-Phe-His-Leu. Brain cathepsin B may have a role in the generation and degradation of angiotensin II in physiological conditions.

Angiotensin I↗
PubMed1985

Comparison of [3H]nicotine and [3H]acetylcholine binding in mouse brain: regional distribution.

In a continuing study of nicotine binding sites, we determined the relative amount of nicotine binding and acetylcholine binding in various brain regions of C57/BL and of DBA mice. Although midbrain showed the highest and cerebellum the lowest binding for both [3H]nicotine and [3H]acetylcholine, the ratio of nicotine to acetylcholine binding showed a three-fold regional variation. Acetylcholine inhibition of [3H]nicotine binding indicated that a portion of nicotine binding was not inhibited by acetylcholine. These results indicate important differences between the binding of (+/-)-[3H]nicotine and that of [3H]acetylcholine.

Acetylcholine↗
PubMed1984

Reduction of dopamine uptake and cocaine binding in mouse striatum by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) (daily injections of 8 mg/kg for 5 days via tail vein) reduced [3H]dopamine uptake in striatal synaptosomes by 63% and reduced [3H]cocaine binding to striatal membranes by 61%. [3H]Cocaine binding was not affected in olfactory tubercle, suggesting a selective effect of NMPTP on the nigro-striatal but not on the mesolimbic dopaminergic system. The destruction of dopamine terminals in the striatum did not alter (up-regulate) [3H]spiroperidol binding. The results suggest that NMPTP causes a degenerative destruction of the striatal dopamine pathway and that NMPTP may be useful in developing a rodent model of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

RNA concentration and protein synthesis in rat brain during development.

As a first approximation of ribosomal concentration we have measured total RNA in some regions of the CNS at different ages and found that the rates of protein synthesis therein are directly proportional to the RNA content. This suggests that the 'RNA activity' remains unchanged during growth and that higher protein synthesis rates in young brain are due to higher content of ribosomal material.

Animals↗
PubMed1984

Endogenous material in brain inhibiting [3H]nicotine and [3H]acetylcholine binding.

The supernatant obtained from mouse brain homogenates contains material that inhibits the saturable binding of [3H]nicotine in mouse cerebral cortex. This inhibitory material was further purified by heat denaturation, ultrafiltration through an Amicon PM-10 membrane filter, and gel chromatography on Sephadex G-10. The material inhibited the binding of [3H]acetylcholine with the same potency as it did that of [3H]nicotine. It also had some affinity for the sites that specifically bind [3H]D-Ala, D-Leu enkephalin, but had much lower affinity for the binding sites for [3H]quinuclidinyl benzilate (QNB), [3H]spiroperidol, [3H]naloxone, or [3H]imipramine. Acid hydrolysis destroyed the activity. These preliminary results suggest the presence in brain of "nicotinelike" substances, one of which may be the endogenous ligand for the sites that specifically bind [3H]nicotine.

Acetylcholine↗
PubMed1984

Beta-adrenergic and muscarinic cholinergic receptors: overlap in their genetic determination.

Significant positive correlation between the ligand binding values for beta-adrenergic receptors and those for muscarinic cholinergic receptors was found in five inbred strains of mice (r = 0.84) and in different vertebrate species (r = 0.99). Comparative analysis of analogous receptor studies done on various brain regions in other laboratories revealed high positive correlation between regional binding values for these two receptors. In conjunction with the work presented here, an overlap in the genetic determination of beta-adrenergic and muscarinic cholinergic receptors is suggested.

Animals↗
PubMed1984

Brain protein synthesis rates are not sensitive to elevated GABA, taurine, or glycine.

The effects of elevated levels of GABA, glycine, or taurine on the rate of protein synthesis in plasma, brain, liver, and muscle of adult mice were measured in in vivo experiments after a flooding dose of labeled valine. Elevation of these amino acids caused hypothermia; keeping the animals in an incubator maintained physiological body temperature. The increase in GABA or glycine did not affect the rate of protein synthesis in these tissues to a significant degree. The increase in taurine levels caused inhibition of valine incorporation in plasma, liver, and muscle, while brain protein synthesis was unaffected. When glycine was increased in brain, the uptake of labeled free valine in the brain was greater.

Animals↗
PubMed1984

Binding of imipramine and cocaine to a model lipid membrane: comparison with binding to brain membranes.

[3H]Imipramine and [3H]cocaine were concentrated at membranes of liposomes prepared from phosphatidylcholine, cholesterol, and dicetylphosphate. This "binding" has an apparent dissociation constant in the micromolar range and a density close to 2 pmol/micrograms of phosphatidylcholine. The potencies of various drugs in inhibiting the binding to liposomes correlated only weakly with those in inhibiting the high-affinity binding of [3H]imipramine and [3H]cocaine to brain membranes. However, there was a highly significant correlation between the potencies of drugs in inhibiting binding to liposomes and their lipophilic character, indicating the involvement of hydrophobic bonding. Although the amounts of phosphatidylcholine and cholesterol in brain preparations in assays for high-affinity binding to brain membranes were in the same range as those used in our assays with liposomes, the inhibition of the high-affinity binding to brain membranes was only weakly dependent upon the lipophilicity of the inhibiting drug. These results indicate that lipophilicity is but one of the factors in the complex binding interactions between lipophilic substances and integral brain membranes. In addition, the results are in agreement with the suggestion that phosphatidylcholine and cholesterol are not the primary sites of high-affinity binding [3H]imipramine and [3H]cocaine to brain membranes, although it cannot be ruled out that these lipids have different properties in natural biological membranes and in artificial liposome membranes.

Animals↗
PubMed1984

Changes in medium radioactivity and composition accompany high-affinity uptake of glutamate and aspartate by mouse brain slices.

In measurements of high affinity transport in tissue slices, the incubation medium is often treated as an "infinitely large pool". External substrate concentrations, even at the micromolar level, are assumed to be constant and metabolic interactions between tissue and medium are neglected. In the present report we describe experiments in which glutamic and aspartic acid uptake by mouse brain slices were studied using techniques that could test these assumptions. Cerebral hemispheres were cut into 0.1 mm sections and about 90 mg of tissue incubated in 10 ml of oxygenated medium. After 45 minutes of equilibration, radioactive substrates were added and the concentrations and specific activities of the amino acids and their metabolites in the medium were determined. During the first 10 min following substrate addition, rapid decreases in glutamic and aspartic acid concentrations in the medium were accompanied by large decreases in specific activity caused by the continuous release of these amino acids from the tissue. In addition, extensive conversion of both substrates to glutamine and the preferential accumulation of this metabolite, in the medium, was found. These results demonstrate that metabolism and release occur simultaneously with uptake during transport experiments in vitro and that these processes can take place in specific tissue compartments. It is therefore necessary to measure the tissue and medium concentration levels of amino acids along with their radioactivity in such experiments, since all three processes (transport, metabolism, and compartmentation) are interrelated in the clearance of amino acids from the incubation medium and probably from the extracellular spaces in vivo as well.

Animals↗
PubMed1984

Glycine potentiates the action of some anticonvulsant drugs in some seizure models.

The anticonvulsant effect of either phenobarbital or dilantin was potentiated by exogenous glycine in DBA/2 audiogenic seizure mice and in 3-mercaptopropionic acid-induced seizures. In seizures caused by pentylenetetrazol, glycine potentiated the anticonvulsant effect of phenobarbital only slightly; in combination with dilantin, which was ineffective by itself, it did not have an effect. Valproic acid, in large doses, prevented 3-mercaptopropionic acid-induced seizures; glycine did not potentiate its effect. Glycine thus potentiates anticonvulsant effects, but only of some drugs and only in some of the seizure models. This suggests that the mechanism of the anticonvulsant effect of glycine is similar to that of some of the anticonvulsant drugs such as dilantin and different from others, and that this mechanism is not effective in all seizure models.

3-Mercaptopropionic Acid↗
PubMed1984

[3H]cocaine binding in brain is inhibited by Tris (hydroxymethyl) aminomethane.

High-affinity binding of [3H]cocaine to membranes of mouse cerebral cortex is inhibited by Tris (hydroxymethyl) aminomethane, the buffer commonly used in receptor binding assays. This inhibition is not due to an effect of ionic strength in general. Comparison of binding in Tris buffer with that in sodium phosphate buffer indicates a more than 4-fold higher Kd in the former buffer, with no differences in the Bmax values.

Animals↗
PubMed1984

Effect of cerebral puncture on brain protein synthesis in adult and young rodents.

In adult mice cerebral puncture results in an inhibition of brain protein synthesis, as suggested previously by Dunn (1975). The inhibition is apparent within a few minutes but subsides by 15 min after puncture. The percent inhibition therefore depends on the length of time between the puncture and the measurement. Mice receiving a puncture were less active than controls, and a decrease in brain temperature was observed in these animals. The decrement is, however, too small to account for the inhibition of synthesis. Diphenylhydantoin had no effect on the inhibition. Cerebral puncture of young mouse (7-day-old) or rat (8-day-old) brain induced no inhibition of brain protein synthesis.

Aging↗
PubMed1984

Protein synthesis rates in rats with portacaval shunts.

Protein synthesis rates were measured (33 days postoperatively) in rats with portacaval shunts and in unoperated controls. In brain, no change in the rate of protein synthesis was evident in shunted rats. These data thus do not support the hypothesis that an inhibition of brain protein synthesis is a factor in the etiology of hepatic encephalopathy. The synthesis rate in forebrain at 82 days of age was 0.52%/h. Though brain wet weight was the same in both groups, rats with shunts grew relatively slowly, and their testicles probably decreased in weight. However, no inhibition of muscle, liver, or testicular protein synthesis could be detected. The mechanism of slower or negative growth in these tissues might thus involve an increase in the degradation rate, although a transient inhibition of synthesis at an earlier period is also possible.

Animals↗
PubMed1984

Similarities and differences between high-affinity binding sites for cocaine and imipramine in mouse cerebral cortex.

Previously we found close similarities between high-affinity binding sites for [3H]cocaine and those for [3H]imipramine in the mouse cerebral cortex in regard to their association with neuronal uptake of serotonin. In the present study we investigated whether the two ligands bind to the same site. The two ligands had the following high-affinity binding properties in common: localization in both synaptosomal and microsomal fractions; vulnerability to treatment with N-ethylmaleimide, trypsin, and phospholipase A2; and resistance to exposure to dithiothreitol. In contrast, cocaine binding in the cerebral cortex was more sensitive to heat inactivation than imipramine binding. In addition, the mechanism by which cocaine inhibited [3H]imipramine binding differed from that by which imipramine inhibited [3H]cocaine binding. These data suggest that the high-affinity binding sites for [3H]cocaine and [3H]imipramine in the cerebral cortex are distinct entities.

Animals↗