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Pharmacological properties of new cyclic derivatives of phenylsuccinimide and their influence on noradrenaline, dopamine, serotonin, 5-hydroxyindoleacetic acid, gamma-aminobutyric acid concentrations and monoaminooxidase activity in animal brains.

Three new cyclic derivatives of phenylsuccinimide (I-10, I-11 and IL-7) were subjected to preliminary pharmacological studies in animals. Minimal peripheral action and inhibitory influence on the CNS were noted (only IL-7) was found to stimulate CNS). Neurotoxic effects were similar to those of the classical succinimides . Anticonvulsant activity and behavioral effects of tested compounds are discussed in the light of their influence on neurotransmitters.

Animals↗

Determination of 5-hydroxytryptophan, serotonin and 5-hydroxyindoleacetic acid in rat and human brain and biological fluids by reversed-phase high-performance liquid chromatography with electrochemical detection.

A rapid and sensitive method for the concurrent determination of 5-hydroxytryptophan, serotonin and 5-hydroxyindole acetic acid by reversed-phase high-performance liquid chromatography with electrochemical detection has been developed. The separation of the indolic compounds was achieved using a phosphate-citric acid eluent containing 5% methanol. Detection limits in the low picogram range were found. The method has been applied to the determination of the indolic compounds in rat and human brain tissues, as well as in human plasma and cerebrospinal fluid. Tissue and plasma preparation required only deproteinization before chromatography, while cerebrospinal fluid was directly applied to the column.

5-Hydroxytryptophan↗

[Effect of prolonged interaction of mice with aggressive and submissive types of behavior on the concentration of serotonin, 5-hydroxyindoleacetic acid and noradrenalin in the brain].

As a result of repeated experience of victories and defeats in mice of C57BL/6 line, submissive and aggressive types of behaviour were elaborated, the stabilization of which was accompanied by a change in serotonin and noradrenaline content in various parts of the brain, at least of two kinds. Nonspecific unindirected changes in transmitter' levels found in both groups of animals in comparison with the control, are apparently due to the experience of zoosocial contracts. Changes were also noted connected with specificity of the observed behaviour.

Animals↗

Postmortem changes of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in mouse brain and their prevention by pargyline and microwave irradiation.

Postmortem (pm) manipulations of brain tissue of decapitated mice produced a maximum decline in 5-HT and a maximum rise in 5-HIAA of 20 and 40%, respectively. The pm treatments included freezing and thawing, mincing, and leaving over. Microwave irradiation or pretreatment of the animals with the enzymatic inhibitors NSD 1015 or pargyline suppressed the pm effects. The possible role of pm effects in the initial accumulation of 5-HT and decline of 5-HIAA in the brain following administration of pargyline was studied. Out data suggest that, when MAO inhibitors are used, 5-HT turnover might be overestimated by pm changes.

Animals↗

The origin of blood k-hydroxyindoleacetic acid following L-hydrazino-alpha-methyldopa (MK-486).

Blood 5-HIAA-14C levels derived from exogenous D,L-5-HTP-14C were investigated in normal, sham-operated and nephrectomized rats pretreated with MK-486 and probenecid (200 mg/kg i.p.). Blood 5-HIAA-14C levels decreased in nephrectomized rats following probenecid. Peripheral decarboxylase inhibition by MK-486 was enhanced by both probenecid and nephrectomy. Increased penetration of 5-HTP into brain occurred following probenecid. The results indicate that following MK-486 about 20% of the blood 5-HIAA-14C derived from 5-HTP-14C in rats originates in the CNS.

5-Hydroxytryptophan↗

The origin of blood 5-hydroxyindoleacetic acid following L-hydrazine-alpha-methyldopa (MK-486).

Blood 5-HIAA-14C levels derived from exogenous D,L-5-HTP-14C were investigated in normal, sham-operated and nephrectomized rats pretreated with MK-486 and probenecid (200 mg/kg i.p.). Blood 5-HIAA-14C levels decreased in nephrectomized rats following probenecid. Peripheral decarboxylase inhibition by MK-486 was enhanced by both probenecid and nephrectomy. Increased penetration of 5-HTP into brain occurred following probenecid. Thr results indicate that the following MK-486 about 20% of the blood 5-HIAA-14C derived from 5-HTP-14C in rats originates in the CNS.

5-Hydroxytryptophan↗

[Effect of hydantoins on urinary excretion of 5-hydroxyindoleacetic acid].

The investigations were carried out in 10 patients with epileptic seizures. The obtained results were compared with those in a control group of 20 healthy subjects. The 24-hour urinary excretion of 5-HIAA efore hydantoinal and on the 1st, 2dn and 3rd days of hydantoinal administration was determined by the method of Udenfried et al. as modified by McFarlane et al. It was found that healthy subjects excreted significantly more 5-HIAA before and after hydantoinal load. Administration of this drug increased significantly the excretion of this metabolite with urine, in healthy subjects but in epileptics it had no significant effect on 5-HIAA level in 24-hour urine.

Adolescent↗

Effect of heat stress on brain 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in some vertebrate species.

1. The variations in 5-HT and 5-HIAA levels following heat exposure and split heat doses were determined in the different brain regions of Gerbillus pyramidum, Streptopelia senegalensis aegyptiaca and Agama stellio. 2. Heat exposure was found to be associated with an increase in the levels of the two indole compounds. 3. The 5-HT concentrations increased markedly in the three species following the first heat dose and decreased following the second dose in the various brain regions except in the cerebellum of Agama. 4. The increased 5-HT levels when animals are exposed to high temperature probably represent a response to activate heat-loss mechanisms and to depress heat production.

Animals↗

Serotonin and 5-hydroxyindoleacetic acid in plasma. Potential use as peripheral measures of MAO-A activity.

We have explored the possibility of using measures of 5-HT (extracellular 5-HT and 5-HIAA in blood) as peripheral indexes of MAO activity. Depressed patients treated with phenelzine for 6 weeks display a dramatic increase of plasma 5-HT (270% of basal values) together with a decrease of plasma 5-HIAA. After treatment with irreversible MAO inhibitors, rat plasma 5-HIAA decreased in a similar fashion than MAO-A activity in liver, lungs and brain, measured using 5-HT as substrate. These results support the use of plasma 5-HT and 5-HIAA in humans to evaluate the action of MAOI on the serotonergic system.

Animals↗

Effect of cold exposure on brain 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in some vertebrate species.

1. The changes in 5-HT and 5-HIAA levels were studied in the brain regions of Gerbillus pyramidum, Streptopelia senegalensis aegyptiaca and Agama stellio following exposure to cold. 2. In general, the 5-HT levels increased in the Gerbillus brain parts and decreased in those of Streptopelia. 3. Cold exposure in the Agama brain regions caused a transient decrease in the 5-HT levels of the cerebral hemispheres, midbrain and pons plus medulla after 6 hr and a general increase after 12, 24 and 48 hr. 4. It is concluded that cold exposure may be associated with increased activity of 5-HT ergic neurons and the rate of turnover of 5-HT to 5-HIAA.

Animals↗

[Spectrofluorometric determination of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in rat diencephalon (author's transl)].

A spectrofluorometric method to determine 5-HT and 5-HIAA in rat diencephalon has been developed, following the criterion of unifying the methodology in determining biogenic amines and their metabolites. Linearity in the method remains in the interval between 0.01 microgram and 0.05 microgram. Recovery is about 70% for amine and about 80% for the metabolite. Highest concentrations of 5-HT appear in one month old female animals, and are significantly higher than those found in the male population of the same age. Concentrations in two month old animals decrease, without significant differences between males and females. Values found for 5-HIAA seem not to change so significantly, although a slight decrease is observed in the elder males.

Age Factors↗

[Behavior of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in relation to agonized suffering (I)].

The authors have studied the levels of 5-HT and 5-HIA,--in serum, CSP fluid and pericardial fluid of cadavers at the Forensic Anatomic Institute of Granada and its relations with the length of agonized suffering. The results showed us that the study of 5-HT and its main metabolite, the 5-HIAA, may be useful for the exact evaluation of agonized suffering, and the pericardial fluid is most suited for the analysis of 5-HT and 5-HIAA. We found that there was a significant correlation between the 5-HT and 5-HIAA and the agonized suffering. When the agonized sufferings of a moderate length (10 min-6h) were compared with the slow and long processes of death, the correlation was highly significant (P less than 0.001).

Forensic Medicine↗

Inhibition of glucose uptake by 5-hydroxyindoleacetic acid in the isolated rat soleus muscle.

Accumulated end-products were identified to participate in the late development of glucose intolerance and insulin resistance (IR) in patients with chronic renal insufficiency. The possible pathophysiological role of accumulated 5-hydroxy-indoleacetic acid (5HIAA) in the genesis of IR was investigated employing an in vitro animal model. 5HIAA inhibited the basal glucose uptake in isolated rat soleus muscle with intact membrane with A50 = 1.25 mumol/l, and Emax = 88.6%. 5HIAA significantly inhibited the insulin, and tolbutamide stimulated glucose uptake. In Ca and Mg depletion 5HIAA showed a partially additive inhibitory effect, while nonadditive inhibitory activity was observed in the case of K+ excess. It is concluded that 5HIAA is a metabolically active end-product interfering with glucose uptake in muscle at an insulin postreceptor level, and its effect is related to Ca modulation in the insulin regulatory cascade.

Animals↗

Serotonin and 5-hydroxyindoleacetic acid levels in discrete hypothalamic areas of the rat brain: relation to circulating corticosterone.

We examined the influence of adrenalectomy (ADX), and chronic corticosterone (CORT) replacement, on serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels in discrete hypothalamic areas of the rat brain. A significant decrease in 5-HT (-25%) and 5-HIAA (-28%) content was observed in the paraventricular nucleus (PVN) 7 days following ADX. A similar decrease in 5-HT levels (-27%) was observed in the preoptic area (POM) following ADX. In contrast, 5-HT and 5-HIAA levels in the supraoptic nucleus (SON) were significantly elevated by 82% and 54%, respectively. Replacement therapy with subcutaneous CORT implants (200 mg) was effective in preventing these effects of ADX in some cases. These findings suggest that the pituitary-adrenal endocrine system may influence various physiological and behavioral functions via its action on serotonergic neurons within specific hypothalamic sites.

Adrenalectomy↗

Relationships between tryptophan in serum and CSF, and 5-hydroxyindoleacetic acid in CSF of man: effect of cirrhosis of liver and probenecid administration.

Tryptophan was measured in the lumbar CSF and serum of patients undergoing neurological investigation (controls) and in patients with hepatic cirrhosis. Samples were taken from the fasting patients at 8:00 a.m. Under these conditions, in the controls the mean CSF, free )mpm-albumin-bound) and total serum tryptophan were in the approximate ratio 1:4:24. In this cross-sectional study, for the controls, CSF tryptophan was correlated significantly and positively with the total serum but not with the free serum tryptophan. In patients with advanced hepatic cirrhosis the mean CSF tryptophan concentration was greatly elevated. However, the mean total serum tryptophan was unchanged and the free serum tryptophan only slightly elevated. Administration of probenecid, which displaces tryptophan from binding sites on serum albumin, and thereby increases the proportion of serum tryptophan in the free form, did not affect CSF tryptophan.

Adult↗

[Interstrain differences in the serotonin and 5-hydroxyindoleacetic acid levels in the postnatal ontogeny of C57BL/6J and BALB/cLac strain mice].

The content of serotonin and 5-hydroxy-indole-acetic acid (5-HIAA) was determined in the brain stem and hemispheres in 1 and 3 months old C57BL/6J and BALB/cLac mice. The characteristic dynamics of serotonin and its metabolite content related to the age was found in different brain regions and proved to be similar in both the strains, but the rate of serotonin system development in C57BL/6J mice was higher than in BALB/c Lac mice. An intensive catabolism of serotonin, possibly, related to the reaction to new environment was noted in the newborn animals. Sex differences in the rate of serotonin system maturation and serotonin and 5-HIAA content were shown for 12--16 days old mice: 12 days old males were characterized by more intensive metabolism than females while 16 days old males had less serotonin than females.

Animals↗

Diurnal patterns of serotonin, 5-hydroxyindoleacetic acid, tryptophan and fibrinolytic activity in blood of depressive patients and healthy volunteers.

Diurnal changes of serotonin-related factors in whole blood and fibrinolytic activity were determined in depressed patients and healthy controls. Whole blood serotonin concentration of depressed patients showed marked changes throughout daytime, with maximum values in the evening and lowest values in the morning, whereas its metabolite 5-HIAA followed a contrary pattern. The circadian rhythm of 5-HT and 5-HIAA in the control group was quite different from depressed patients. Plasma levels of tPA decreased from 12:30 to 16:30. Concentrations of free plasminogen activator inhibitor (PAI-1) and complex of tPA-PAI-1 decreased from 8:30 to 16:30. Plasma levels of total PAI-1 decreased from 8:30 to 16:30. Plasma levels of the fibrinolytic parameters may be lower in depressive patients than in normal controls. These results support the changes in the circadian rhythm of serotonin and its related substances in the blood of depressive patients.

Adult↗

[Fluorescent method of determining serotonin deaminating monoamine oxidase activity based on the amount of 5-hydroxyindoleacetic acid].

A fluorimetric procedure is developed for estimation of serotonin deaminating activity of MAO by measuring the oxidized reaction product-5-hydroxyindolyl acetic acid (5-HIAA) extracted from acid solution by means of diethyl ester with subsequent transfer in 0.1 M phosphate buffer, pH 7.3. The optimal conditions for the extraction were developed, ensuring the maximal yield of 5-HIAA and serotonin. Low content of serotonin was found in the phosphate buffer. The concentration of serotonin was similar both in test and control samples; it did not interfere with the estimation of 5-HIAA. Sensitivity and reproducibility of 5-HIAA estimation by means of its fluorescence in 3 N HCI was higher as compared with the reaction with o-phthalic dialdehyde. Yield of 5-HIAA extracted from solution was approximately 90%. Activity of MAO, as shown by reaction of 5-HIAA with o-phthalic dialdehyde, was equal to 2.81 +/- 0.19 nM/mg/min (n = 15) and - by fluorescence in 3 N HCL - 2.92 +/- 0.29 nM/mg/min (n = 12).

Animals↗