Effect of Neurotropic and Immunotropic Drugs on Leukocyte Elastase Activity In Vitro.

Leukocyte elastase is a marker of inflammation. Previously, a relationship was found between the severity of mental disorders in patients and elastase-like activity of blood plasma. The effect of various neurotropic drugs on leukocyte elastase activity was analyzed in an in vitro experiment. We revealed an inhibitory effect of the benzodiazepine tranquilizers diazepam and bromodihydrochlorophenylbenzodiazepine and immunomodulators aminodihydrophthalazinedione and diclofenac on the plasma elastase-like activity of healthy donors and pure human neutrophil elastase. The antipsychotics chlorpromazine and alimemazine, as well as the nootropic vinpocetine increased elastase-like activity in a dose-dependent manner. The activating effect of chlorpromazine and vinpocetine, but not alimemazine, was reproduced in neutrophil elastase. We hypothesized that these drugs can affect the development of inflammatory reactions in the complex therapy of mental disorders.

Assessment of the Cytotoxicity of Peptide Modifications of Doxorubicin on Tetrahymena pyriformis.

The cytotoxicity of doxorubicin (Dox) and its peptide modifications Z-Gly-Pro-Dox and Boc-Gly-Pro-Dox were studied. Tetrahymena pyriformis was used as a test system, which made it possible, due to the short life cycle and high reproduction rate of ciliates, to trace their response to the effects of toxicants over several generations. It was found that peptide modification of the Dox molecule markedly reduces its cytotoxic and cytostatic effect. The Z-Gly-Pro-Dox modification has less cytotoxic and cytostatic effect compared to Boc-Gly-Pro-Dox. When determining the ability of drugs (at a concentration of 100 µM) to prevent bacterial contamination of samples, it was shown that the smallest degree of overgrowth was recorded in the presence of Dox (OD600nm 81.1). Boc-Gly-Pro-Dox also had a bacteriostatic effect, though less pronounced (OD600nm 93.8). The degree of overgrowth in the presence of Z-Gly-Pro-Dox was close to that of distilled water. The results obtained on ciliates did not contradict the data obtained in similar studies on mice.

Neurotropic peptide HLDF-6-amide reduces age-related decline in sexual activity in old male rats.

Aging is associated with a decline in the erectile capacity and sexual motivation. Emerging new therapy for the treatment of these age-related pathologies in men is the use of the regulatory peptides. We validated the use of HLDF-6-amide (Thr-Gly-Glu-Hse-His-Arg-NH2) as a potential modulator of sexual performance in aged male rats. Behavioral tests, including the standard parameters of sexual behavior, were performed longitudinally at 20 and 26 months of age. The effects of HLDF-6-amide administered daily at 300 µg/kg for 3 week on the levels of sex hormones and the activity of antioxidant enzymes and indicators of inflammation were evaluated. HLDF-6-amide administration increased the copulative activity of the 20-month-old male rats. This effect of HLDF-6-amide was more pronounced in the 26-month-old rats. Although HLDF-6-amide did not have the effect on the levels of circulating testosterone and estradiol, it reduced the activity of leukocyte elastase and glutathione-S-peroxidase, suggesting that the peptide has anti-inflammatory and antioxidant properties. Therefore, this study shows that HLDF-6-amide has the positive impact on sexual activity in this rodent model, representing a new therapeutic approach for improving sexual performance in older men.

Functional Connectomic Approach to Studying Selank and Semax Effects.

The present study was aimed at the assessment of effects of anxiolytic Selank and nootropic Semax on the whole-brain resting-state functional connectivity (FC) of each of the predefined regions of interest (ROIs) in 52 healthy participants. The ROIs included amygdala (one of the key regions for the regulation of anxiety) and dorsolateral prefrontal cortex (DLPFC; the key region for executive functions, including working memory) in the right and left hemisphere. Resting-state fMRI was carried out three times, namely before, after 5 and 20 min of the injection of either Semax, or Selank, or placebo. Between-group alongwith between-condition differences were revealed in FC between the right amygdala and a region in fusiform, inferior and middle temporal as well as parahippocampal gyri in the right hemisphere. Post hoc analysis allowed us to define both general and specific effects of Selank and Semax on FC between the right amygdala and the right temporal cortex for the first time.

Effects of Semax on the Default Mode Network of the Brain.

The effects of nootropic drug Semax on the neuronal network of the brain were studied by the resting state functional magnetic-resonance imaging (resting state fMRI). The study was carried out on two groups of healthy volunteers (11 men and 13 women aged 43.9±9.5 years). Resting state fMRI was carried out 3 times: directly before and 5 and 20 min after intranasal 1% Semax (14 subjects) or placebo (10 subjects). The topography of the resting state default mode network was studied. A greater volume of the default mode network rostral (medial frontal cortex) subcomponent was detected in the Semax group in comparison with controls. Resting state fMRI confirmed Semax effects on the neuronal network of the brain and demonstrated topography of these effects.

[Optimization of the treatment of anxiety disorders with selank].

AIM: To compare the efficacy and tolerability of monotherapy with phenazepam to complex treatment with the peptide preparation selank and phenazepam in patients with anxiety disorders. MATERIAL AND METHODS: Authors explored the anxiolytic effect and tolerability of monotherapy with phenazepam (30 patients) and complex treatment with selank and phenazepam (40 patients) in anxiety-phobic, hypochondriac and somatoform disorders (ICD-10 items F40.2-9, F41.1-9, F45.0-2). Therapeutic effect was assessed clinically and with HDRS, CGI and Spilberger scales. Tolerability was evaluated using the UKU scale. Stroop test and verbal fluency test were used. Quality of life was assessed with the SF-36. RESULTS: The positive effect of phenazepam was achieved earlier in the optimization of treatment with selank on HDRS. The combined treatment decreased the level of undesirable side-effects of phenazepam (attention and memory impairment, asthenia, sedation, increase in sleep duration, sexual disturbances, emotional indifference and orthostatism) during the course of treatment and after the tranquilizer withdrawal. Taken together, the therapeutic efficacy and reduction of side-effects had a positive impact on the quality-of-life of the patients treated with selank as add-on to phenazepam. CONCLUSION: The results extend therapeutic possibilities of treatment of anxietyspectrum disorders with the combination of benzodiazepine tranquilizers and selank.

Dipeptidylpeptidase 4 (DPP4, CD26) activity in the blood serum of term and preterm neonates with cerebral ischemia.

BACKGROUND: To investigate the mechanisms of inflammation in neonates after cerebral ischemia (CI), we evaluated the DPP4 activity in their blood sera and compared these values with clinical indicators. METHODS: The activity of DPP4 was determined in blood serum by a fluorescent method. We studied the correlation between the blood serum DPP4 activity and clinical, neurological and biochemical parameters in neonates with CI. RESULTS: No correlation between the DPP4 activity in umbilical blood and the venous blood of mothers was discovered. Increased blood serum DPP4 activity in full-term and pre-term newborns with CI is demonstrated. The interrelation between serum DPP4 activity and the functional disturbances of CNS (such as depression or excitement) was found in mature but not in premature newborns. Enzyme activity was still elevated at 2-3weeks after birth. CONCLUSION: It is possible that in neonates this enzymatic system operates independently from mothers. It is assumed that increased DPP4 activity in newborns with CI is apparently connected with immune system activation in response to hypoxic stress. The obtained data support the participation of DPP4 in adaptive reactions of newborns and its regulating influence during hypoxemic damage of the CNS due to inflammation and neurodegeneration.

Neurotensin-like peptides as potential antipsychotics: modulation of the serotonin system.

Neurotensin-like peptides acting as functional antagonists of serotonin receptors were revealed in the head-shaking test on mice. The neurotensin-like peptides block the serotonin-induced platelet aggregation in humans. Radioligand binding assay showed that neurotensin-like peptides modulate specifi c binding of 5НТ2 serotonin receptor antagonist ketanserin, but have no effect on binding of ligands of 5HT2c receptor mesulergine and 5HT1а receptors NAN-190. Similar effects of neurotensin-like peptides in the experiments in vivo and in vitro suggest that the mechanisms of the detected antipsychotic effect of the peptides can be mediated by serotonin receptors.

Effects of Pro-Gly-Pro tripeptide on the dopamine system.

Tripeptide Pro-Gly-Pro interacted with dopamine receptors in vitro and reduced behavioral manifestations of apomorphine-induced hyperfunction of the dopamine system in verticalization, stereotypy, and yawning tests. Presumably, the behavioral effects of Pro-Gly-Pro tripeptide were mediated through post- and presynaptic D(2)and D(3)receptors.

Naloxone-blocked depriming effect of anxiolytic selank on apomorphine-induced behavioral manifestations of hyperfunction of dopamine system.

Peptide anxiolytic selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) applied intraperitoneally in doses of 0.01, 0.1, 1.0, and 10.0 mg/kg to mice reduces behavioral manifestations of dopaminergic system induced by apomorphine in the verticalization test. This effect was comparable to that of atypical antipsychotic olanzapine in near-therapeutic doses (0.1 and 1.0 mg/kg, intraperitoneally) and was blocked with nonselective opioid receptor antagonist naloxone (10 mg/kg, intraperitoneally). Radioreceptor assay showed that selank did not displace nonselective D2-dopamine receptor antagonist (3)H-spiperone (EC50>100 microM) and delta- and micro-opioid receptor ligand 3H-DADLE (EC50>40 microM) from specific binding sites on rat brain membranes. It is hypothesized that the revealed behavioral effect of selank is mediated by its modulating effect on the endogenous opioid system and specifically, by its effect on activity of enkephalin-degrading enzymes.

Reactions between beta-casomorphins-7 and 5-HT2-serotonin receptors.

Radioreceptor analysis showed that human beta-casomorphin-7 displaced 3H-spiperone from 5-HT2-serotonin receptors of the rat cerebral frontal cortex: EC50 8 +/- 1 microM. Human and bovine beta-casomorphin-7 dose-dependently blocked serotonin-induced human platelet aggregation: IC50 5 +/- 1 and 20 +/- 4 microM, respectively. It was proved that beta-casomorphins-7 act as 5-HT2-serotonin receptor antagonists; one of the mechanisms of their biological effects is presumably associated with modulation of the serotoninergic system.

Half-life of leu-enkephalin in the serum of infants of the first year of life on different types of feeding: relationship with temperament.

The half-life of leu-enkephalin in the serum of infants aged under 1 year is significantly shorter than in adults. In girls leu-enkephalin half-life is significantly longer than in boys. The half-life of leu-enkephalin is different in infants on breast and formula feeding. Nine characteristics of temperament in infants of the first year of life were determined using EITQ and ITQ questionnaires. Serum leu-enkephalin half-life directly correlated with temperament characteristics (activity, perception, threshold), but not with the level psychomotor development.

[Effect of therapy with lisinopril on the state of cerebral blood flow in women with hypertension in peri- and postmenopause]. / Vliianie terapii lizinoprilom na sostoianie tserebral'nogo krovotoka u zhenshchin s arterial'noi gipertenzieiv peri- i postmenopauze.

Blood flow in extra and intracranial arteries was assessed by doppler ultrasound in 26 hypertensive women without history of stroke. Studies were performed before treatment, after acute test with lisinopril and in 1 month of therapy with lisinopril. Baseline investigation revealed changes of velocity characteristics of blood flow and resistance indexes indicative of impaired cerebral hemodynamics both at extra- and intracranial level. After treatment with lisinopril signs of improvement of blood flow in extra- and intracranial arteries were found. Most important finding was normalization of ability of extracranial arteries to spasm and dilation presumably associated with restoration of hemodynamic reserve of cerebral vessels.

Effects of Selank on behavioral reactions and activities of plasma enkephalin-degrading enzymes in mice with different phenotypes of emotional and stress reactions.

Comparative study of plasma activities of enkephalin-degrading enzymes in mice with different phenotypes of emotional and stress reactions revealed significant differences between intact BALB/c and C57Bl/6 mice by the half-life of plasma leu-enkephalin. Selank in a dose of 100 micrograms/kg produced an anxiolytic effect in the open-field test and increased the half-life of plasma leu-enkephalin in BALB/c mice, but had no effect on behavioral reactions and enkephalinase activities in C57Bl/6 mice. Our results suggest that anxiolytic activity of Selank is associated with inhibition of enkephalin-degrading enzymes.