P. M. Klodt

Disrupted Serotonergic and Sympathoadrenal Systems in Patients with Chronic Heart Failure May Serve as New Therapeutic Targets and Novel Biomarkers to Assess Severity, Progression and Response to Treatment

Background: It is well established that the serotonergic system (SS) plays important roles in the pathogenesis of cardiovascular diseases. However, the impact of serotonin and its inter-relation with the sympathoadrenal system (SAS) in chronic heart failure (CHF) is poorly understood. Methods: Utilizing high-performance liquid chromatography with electrochemical detection, we determined blood plasma levels of serotonin (5-hydroxy-triptamine, [5-HT]p), 5- hydroxy-indole-acetic acid ([5-HIAA]p), epinephrine ([E]p), norepinephrine ([NE]p), 3,4-dihydroxy-L-phenyl-alanine ([DOPA]p), dopamine ([DA]p) and the platelet concentration of serotonin ([5-HT]pt) in CHF patients with different morphofunctional alterations of myocardium. The morphofunctional alterations included diastolic dysfunction (DD), diastolic dysfunction with left ventricular hypertrophy (DD&LVH), and diastolic and systolic dysfunction (D&SD). Results: All CHF groups showed significant rises of [5-HT]p and [5-HT]pt. DD&LVH and D&SD individuals also had increased [5-HIAA]p. Levels of SAS blood biomarkers were also significantly changed. The correlation between SS and SAS was increased in CHF and corresponded with disease severity. Conclusions: These results clearly demonstrate that in CHF patients significant changes in SS and SAS occur, which are thought to relate to the morphofunctional alterations of myocardium. The observed changes in the levels of these biomarkers may serve as potential surrogates to monitor severity of disease, to evaluate response to drug treatment, and as a rational basis for new therapeutic approaches.

The effects of irradiation by 12C carbon ions on monoamine exchange in several rat brain structures

Rats were irradiated with carbon ions (12C) in a Nuklotron accelerator. The irradiation dose was 1 Gy, the energy of the ions was 500 MeV/nuclon, and the linear energy transmission (LET) was 10.6 keV/micron. The animals were decapitated 1 day after irradiation. We isolated the prefrontal cortex, nucleus accumbens, hypothalamus, hippocampus, and striatum, where we determined the concentrations of monoamines and their metabolites. Strong changes were observed in three structures, viz., the prefrontal cortex, nucleus accumbens, and hippocampus. However, significant changes were found in the prefrontal cortex and weaker changes were seen in the nucleus accumbens, whereas changes were insignificant in the hippocampus. This reaction may be related to the fact that the animals were examined on the 2nd day after irradiation. It was shown that an increase in the interval between irradiation and examination of animals results in enhancement of the effects of radiation treatment. The experiments revealed the high sensitivity and reactivity of the prefrontal cortex, which we relate to the key role of this structure in vitally critical processes of behavior.

Effect of space flight factors simulated in ground-based experiments on the behavior, discriminant learning, and exchange of monoamines in different brain structures of rats

Experimental treatment (long-term fractionated γ-irradiation, antiorthostatic hypodynamia, and the combination of these factors) simulating the effect of space flight in ground-based experiments rapidly restored the motor and orienting-investigative activity of animals (rats) in “open-field” tests. The study of the dynamics of discriminant learning of rats of experimental groups did not show significant differences from the control animals. It was found that the minor effect of these factors on the cognitive performance of animals correlated with slight changes in the concentration of monoamines in the brain structures responsible for the cognitive, emotional, and motivational functions.

The behavior and neurotransmitter contents in brain structures of rats with Alzheimer’s disease modeled by administration of Aβ25–35

We studied behavioral and neurochemical alterations that were induced by modeling of Alzheimer’s disease (AD) using bilateral intracerebroventricular administration of Aβ25–35 at a dose of 7.5 nmol in each ventricle. After 5.5 weeks, cognitive and psychoemotional alterations in the Morris spatial learning and Porsolt’s forced-swim tests were observed in rats with strong symptoms that are typical of AD. Measurement of the contents of monoamines and their metabolites in rat-brain structures was performed using the HPLC with the ECD method 1 day after the end of the tests. In the dorsal striatum, we found a decrease in the contents of metabolites of dopamine (DA), including homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 3-methyltyramine (3-MT), and a decrease in the indices of DA utilization, including DOPAC/DA and HVA/DA, whereas the DA content was stable in this structure. In the nucleus accumbens (NA, ventral striatum), we found a decreased level of the HVA/DA ratio, which reflects the lower turnover of extracellular DA. We also found a lower turnover of serotonin (5-HT), which was seen as a decrease in the 5-hydroxyindolacetic acid (5-HIAA)/5-HT ratio, whereas the 5-HT content was elevated. In the hypothalamus, we revealed a significant decrease in the DA level and the levels of its metabolites, including 3-MT and HVA, and 5-HT turnover. We found that Aβ25–35 influenced the indices of amino-acidergic neurotransmission, which was reflected by the higher glutamate content in the striatum. Our data show that cerebral neurotransmitter systems, such as the tuberoinfundibular, mesolimbic, and nigrostrial dopaminergic and the striatal serotonergic and glutamatergic systems, are involved in pathophysiological mechanisms of the development of cognitive and psychoemotional impairments that occur in AD, as modeled by administration of Aβ25–35.

The distribution of monoamines and their metabolites in the brain structures of rats at later periods after exposure to 12C ions

We investigated the levels of monoamines and their metabolites in certain brain structures of rats at 30 and 90 days after exposure to carbon ions (12C) with an energy of 500 MeV/nucleon. The linear energy transfer and radiation dose were 10.6 keV/µm and 1 Gy, respectively. The concentrations of substances were measured in five structures of the brain, including the prefrontal cortex, nucleus accumbens, hypothalamus, hippocampus, and striatum. On day 30 after the exposure, the most pronounced changes in the concentration of monoamines and their metabolites were observed in the nucleus accumbens; the smallest changes were found in the hippocampus and striatum. After 90 days, significant changes were still present in the nucleus accumbens. At the same time, these changes became less evident in other structures. A comparison of our results with the data of similar previous experiments (24 hours after exposure) showed that the most pronounced effect was observed soon after radiation exposure. The induced damage diminished at a later period. Based on the results of our study, we made the hypothesis that the change in the metabolism of monoamines may be compensated if the linear-energy transfer values were relatively low (10.6 keV/μm). At higher values of linear-energy transfer, compensatory and regenerative processes did not occur; the effect increased with time. An increased susceptibility of the nucleus accumbens was found at all the time points after the exposure, which may indicate an important role of this brain structure in the radiation-induced impairment of cognitive functions and emotional and motivational states.

The relationship between the anxiolytic action of selank and the level of serotonin in brain structures during the modeling of alcohol abstinence in rats

We studied the in vivo effects of the peptide anxiolytic selank (0.3 mg/kg) on the behavioral parameters of the syndrome of alcohol withdrawal and the neurochemical indices of the serotonergic system in the brain structures in ex vivo experiments in outbred rats with a preference for a 10% solution of ethanol. We found that a single administration of selank eliminates the anxious response in the elevated plus maze at 48 h after the withdrawal of ethanol and increases the time spent in the open arms and the number of entries into the open arms. Using HPLC, we showed that selank prevents an increase in the serotonin level in the frontal cortex, hypothalamus, and amygdala, which may be related to a decrease in the synthesis of serotonin. The data we obtained indicate that selank has anxiolytic activity under conditions of alcohol abstinence, which suggests that the sphere of its use in clinical practice may be widened.

Effects of Antiglutamate Antibodies on the Development of Stress Response and Neurotransmitter Content in the Hippocampus and Hypothalamus of Rats with Different Behavioral Activity

We studied the effects of intranasal administration of antiglutamate antibodies on the development of stress response and level of neurotransmitter amino acids and monoamines in brain structures of rats with different initial behavioral activity. The stress exposure was followed by significant changes in behavioral activity and concentration of neurotransmitters in rat hippocampus and hypothalamus. The changes in the level of neurotransmitter amino acids and monoamines were more pronounced in the hippocampus. Antiglutamate antibodies administered intranasally in a single dose of 250 μg/kg immediately after stress exposure prevented the development of the stress response and normalized the level of neurotransmitters in the brain structures of rats. The effect of antibodies was the most pronounced in behaviorally active rats.

Increased concentrations of serotonin and 5-hydroxyindoleacetic acid in blood plasma from patients with pulmonary hypertension due to mitral valve disease.

Serotonin content in the plasma and platelets and 5-hydroxyindoleacetic acid concentration in the plasma were shown to increase in patients with pulmonary arterial hypertension due to mitral valve disease. A positive correlation was found between the severity of pulmonary arterial hypertension and concentrations of serotonin (r=0.48) and 5- hydroxyindoleacetic acid in the plasma (r=0.9).

The Effects of Himantane and Cycloprolylglycine on the Enzymatic Linkage of Monoamine Synthesis in the Rat Brain

Using HPLC we studied the effects of new substances with antiparkinsonian activities, viz., himantane and cycloprolylglycine (CPG), on the contents of monoamines and their metabolites in the brain structures of Wistar rats under conditions of the inhibition of tyrosine and tryptophan hydroxylases. It was shown that 70 min after administration himantane induces a significant decrease in the level of noradrenaline in the nucleus accumbens (NA) and striatum. At 70 min after administration of CPG, we observed an increase in the DOPAC/DA ratio in the NA and the level of 5-HIAA in the striatum. At 24 h after CPG administration, we observed an increase in the HVA content and HVA/DA ratio in the hypothalamus and striatum. We found a decrease in 5-HIAA in all brain structures we studied at 24 h after administration of CPG, which was absent at 70 min after injection of the substance; the magnitude of 5-HIAA/5-HT decreased in the hypothalamus, nucleus accumbens, and hippocampus. Our results suggest that both substances we studied influence serotonergic transmission by inhibition of the MAO B enzyme.

Effects of Neurotensin Dipeptide Analog Dilept on Dopamine Metabolism and Synthesis in the Nucleus Accumbens of Wistar Rats

We studied the effects of neurotensin dipeptide analog Dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) on dopamine metabolism and synthesis in the nucleus accumbens of Wistar rats. Dilept increased the levels of dopamine and its metabolites (homovanillic acid and dioxyphenylalanine) and stimulated dopamine turnover in this structure. Dilept accelerated dopamine synthesis under conditions of pulsed activity blockade in dopaminergic neuron by injection of γ-butyrolactone combined with inhibition of aromatic acid decarboxylase with 3-hydroxybenzylhydrazine. The spectrum of pharmacological activities of Dilept towards the dopaminergic system of the nucleus accumbens was similar to that of atypical neuroleptics and neurotensin (endogenous antipsychotic).