[The antiepileptic effects of the combined action of the new 1,4-dihydropyridine derivative glutapyrone with sodium valproate and phenobarbital]. / Antiépilepticheskie éffekty sochetannogo vozdeistviia novogo proizvodnogo 1,4-digidropirina glutapirona s val'proatom natriia i fenobarbitalom.

Antiepileptic effects of a novel amino acid-containing 1,4-dihydropyridine glutapyrone and sodium valproate during combined therapy on generalized pentylenetetrazol- and focal 4-aminopyridine-induced epileptic activity in rat brain cortex were studied, as were combined effects of glutapyrone and phenobarbital on maximal electroshock in mice. The results of these investigations suggest that combined treatment by glutapyrone and sodium valproate or phenobarbital is reasonable and helps potentiate the effect of each drug, thus significantly reducing their doses, and minimize the risk of side effects of the drugs id used in higher doses in case of long treatment.

[The effect of the new amino acid-containing 1,4-dihydropyridine glutapyrone on penicillin-induced focal epileptic activity and convulsions induced by bicuculline and thiosemicarbazide]. / Vliianie novogo aminokislosoderzhashchego 1,4-digidropiridina glutapirona na fokal'nuiu penitsillinindutsirovannuiu épilepticheskuiu aktivnost' i sudorogi, vyzvannye bikukullinom i tiosemikarbazidom.

The experiments on focal penicillin-induced epileptic activity in the brain cortex (Wistar rats) and bicuculline- and thiosemicarbazide-induced seizures (Icr:Icl mice) showed that the glutapyrone possessed a significant antiepileptic activity. As previously shown, that glutapyrone has an influence on 45Ca2+ uptake by rat cortical synaptosomes (evoked by K+ depolarization) as compared with nifedipine and nimodipine, and it was effective in pentylenetetrazol-induced seizures in rats and mice. The mechanism of action of convulsants is associated with the disturbance of different links of GABAergic inhibition. It is suggested that the antiepileptic effects of glutapyrone are realized at least in part by the participation of GABAergic system.

[Studies of kinin-like properties of a new peptide isolated from bovine brain]. / Issledovanie kininopodobnykh svoistv novogo peptida, vydelennogo iz mozga krupnogo rogatogo skota.

Kinin-like properties of two new peptides NRP-11 and P7 which have structural similarity with neurotensin (NT) and kallidin (K) were investigated. It was found that, unlike NT and K, the new peptides possess reduced myotropic and hypotensive activity. On the other hand, similarly to NT and K, the new peptides exhibited a high histamine-releasing activity in rat peritoneal mast cells. Possible central effects are implied for peptide NRP-11 isolated from bovine brain and its fragment P7.

[Anti-epileptic effect of the new calcium channel blocker IOS-1.1212]. / Antiépilepticheskie éffekty novogo blokatora Ca-kanalov IOS-1.1212.

In experiments on freely moving male Wistar rats it was shown that IOS-1.1212 (1,4-dihydropyridine) in a dose 2 and 10 mg/kg (i. p.) suppressed the penicillin-induced focal epileptic activity in cerebral cortex. Similar suppressing effect of IOS-1.1212 was shown on acute generalized tonic-clonic pentylenetetrazol (PTZ) seizures (75 mg/kg i. p.) and on chronic PTZ administration (PTZ-kindling, 30 mg/kg i. p. during 30 days): when injected 30 min before each PTZ administration it delayed the development of kindling-induced seizures susceptibility in randomized animals (series 1) and attenuated the severity of seizures in PTZ-sensitive animals (series 2). However, IOS-1.1212 had no effect on the strychnine-induced focal epileptic activity. In male Icr:Icl mice IOS-1.1212 in a dose 1.5 and 5 mg/kg also influenced the PTZ convulsions (i. v. titration of 1% solution at a rate of 0.01 ml/s) and had no effect on the strychnine convulsions (i. v. titration of 0.01% solution at a rate of 0.01 ml/s) and on maximal electroshock. In addition, IOS-1.1212 significantly increased antiepileptic effect of phenobarbital on maximal electroshock.

[The adrenergic mechanisms of the inhibition of the gastric acid-forming function in acute stress]. / Adrenergicheskie mekhanizmy tormozheniia kislotoobrazuiushchei funktsii zheludka pri ostrom stresse.

It was demonstrated in experiments on Wistar rats that blockade of central adrenergic structures by thymopentin and beta-adrenergic receptors by inderal prevents stress inhibition of hydrochloric acid secretion. Normalization of the antioxidative protection of the stomach which prevents activation of the processes of free-radical oxidation in it plays an essential role in the mechanism of the stress-protective effect of adrenergic influences blockade on the gastric acid-producing function.

[The immunomodulating action of thymopentin in acute and chronic stress]. / Immunomoduliruiushchee deistvie timopentina pri ostrom i khronicheskom stresse.

Thymopentin, an active centre of the thymic hormone, was shown to possess a marked immunomodulatory effect on the cellular immune reactions of immunity in rats under acute and chronic stress. Thymopentin ensures adaptation of the organs of immunogenesis by increasing viability of the polymorphonuclear leukocytes and normalization of the phagocytic activity of the leukocytes.

[Cyclic analogs of bradykinin, containing a carboxyl group]. / Tsiklicheskie analogi bradikinina, soderzhashchie karboksil'nuiu gruppu.

1 alpha-beta-carboxypropionyl-cyclo(9----1 epsilon)-[Lys1, Gly6]bradykinin (Suc-c[Lys1, Gly6]B), 1 alpha-beta-carboxypropionyl-cyclo(10----1 epsilon)kallidin (Suc-cK), cyclo(10 gamma----1 epsilon)-[Glu10]kallidin (c[Glu10]K) and cyclo(11 gamma----1 epsilon)kallidylglutamic acid (cKG) were synthesized. Suc-c[Lys1, Gly6]B and Suc-cK were prepared by acylating the appropriate cyclopeptides with succinic anhydride. c[Glu10]K and cKG were obtained by the classic peptide synthesis, the cyclization being carried out with 61 and 42% yields, respectively. The protecting groups were then eliminated by catalytic hydrogenation. c[Glu10]K and cKG exerted myotropic action on isolated rat uterus (alpha 0.73 and 0.89, pD2 6.61 and 8.61, respectively). cKG displayed direct myotropic activity with respect to electrically stimulated rat vas deferens and guinea-pig ileum, potentiating the contractions (by 100%) in response to electric stimuli. c[Glu10]K and cKG elicit histamine release in isolated rat mast cells (EC30 4.91.10(-5) and 1.47.10(-6) M, respectively). Both cyclopeptides alter arterial pressure following intravenous administration to anaesthetized rats, cats and dogs and affect heart rate. In all assays cKG is more active than c[Glu10]K. Suc-c[Lys1, Gly6]B and Suc-cK do not possess myotropic, histamine-releasing or hypotensive activity, though they were found to elicit a transient increase of bloodflow in cats and dogs.

[Effect of a Ca-channel blocker, ryodipine, on focal and generalized epileptic activity]. / Vliianie blokatora Ca-kanalov riodipina na ochagovuiu i generalizovannuiu épilepticheskuiu aktivnost'.

The experiments were performed on 102 freely moving Wistar rats. Epileptic foci were produced by the application of a filter paper soaked in a sodium benzylpenicillin solution (20,000 IU/ml) onto sensorimotor cortex. It was shown that an intraperitoneal administration of ryodipine (1,2 and 5 mg/kg) during a steady epileptic activity (EA) resulted in suppression of EA in most animals. Antiepileptic effect of ryodipine was manifested by a decreased frequency and amplitude of interictal discharges and a less frequent appearance of ictal discharges (ID). Prior administration of ryodipine (2 mg/kg) 30 min before producing the focus of EA resulted in an increased latency and decreased number of ID, and shortening of the duration of the focus of EA. Generalized convulsions were induced by intraperitoneal of pentylenetetrazol (60 mg/kg). Ryodipine (2 mg/kg, 30 min before pentylenetetrazol) increased latency to first convulsive episodes and delayed the development of generalized tonic-clonic seizures.

[Correction of lipid peroxidation in stress with the peptide bioregulator thymopentin]. / Korrektsiia perekisnogo okisleniia lipidov pri stresse peptidnym bioreguliatorom timopentinom.

Experiments on rats subjected to acute stress have revealed protective effect of thymopentin pentapeptide on somatic disorders and the state of the antioxidation system and the processes of lipid peroxidation in blood and brain.

[The protective action of thymopentin on stress damage to the stomach]. / Zashchitnoe deistvie timopentina na stressornoe povrezhdenie zheludka.

The influence of peptide thymopentin on ulcer effects of the stomach mucous membrane in rats and the state of its processes in acute and chronic stress as well as their combination influence were investigated. The intercommunication of frequency of the formation of ulcer and the activity of superoxide dismutase in stomach fibers was established. Thymopentin displayed a marked antiulcerogenic effect in all kinds of stress.

[The structural organization of interferon molecules as precursors of immuno- and neuroactive oligopeptides]. / Strukturnaia organizatsiia molekul interferonov kak predshestvennikov immuno- i neiroaktivnykh oligopeptidov.

The oligopeptides effecting signalling functions are postulated to emerge from protein precursors by limited proteolytic cleavage in close vicinity to appropriate cell receptors. A variety of immunological activities of interferons are probably mediated by this mechanism. The C-terminal tripeptides liberated from IFN-alpha in limited proteolysis reactions may result in a variety of polarins eliciting a wide spectrum of immunoregulatory effects, which in combination with the antiviral activity of IFN are responsible for effective defense mechanisms in the organism.

[Thymus hormones--precursors of new psychoneuromodulatory peptides]. / Timusnye gormony--predshestvenniki novykh psikhoneiromoduliruiushchikh peptidov.

The influence of thymic hormone's short fragments: thymopentin or T-5 (RKDVY), RKD and SKD, on behaviour and neurochemical processes (contents of GABA and monoamines in the brain and adrenals, plasma corticosterone), was investigated. The 100 and 500 micrograms/kg doses i.p. prevented alterations in rat's brain GABA content and plasma corticosterone level, as well as elicited anxiolytic activity in a conflict test. T-5 exerted antidepressant activity, too. SKD potentiated the haloperidol-induced catalepsy. The data obtained suggest a multicomponent (CNS-activating and inhibiting) mechanism of action of the thymic hormone fragments. These fragments seem to be formed endogenously during thymic hormone bioprocessing and may act as regulatory neuropeptides.

Comparative studies on the central effects of the angiotensin II analogue (Sar1 azaVal3 Ile8) AT II.

The effects of the newly-synthesized AT II analogue (Sar1 azaVal3 Ile8) AT II were investigated in comparison with the octapeptide AT II and the analogue saralazin (Sar1 Ala8) AT II, using intracerebroventricular administration, with respect to the following parameters: the level of biogenic monoamines (DA, NA and 5-HT) and the metabolites HVA and 5-HIAA in mouse forebrain; the behaviour of the animals--cataleptogenic actions of mice, PTZ convulsive--seizure threshold in mice, apomorphine stereotypy in rats and behaviour of rats in a conflict situation. The analogue (Sar1 azaVal3 Ile8) AT II, unlike saralazin and AT II, was found to induce a rise in the NA and 5-HT levels, causing also catalepsy that is different from the catalepsy induced by saralazine, AT II and haloperidol, because of its rapid onset and decline; it increases the PTZ convulsive--seizure threshold and reduces the number of punished responses to the conflict drinking test (anxiomimetic effect) in a dose 20 times lower than the dose inducing the remaining effects. This effect was antagonized by saralazine. It is concluded that the newly-synthesized analogue (Sar1 azaVal3 Ile8) AT II induces effects similar to those caused by AT II, being at the same time different to a certain extent from the effects (quantitative and qualitative) of octapeptide AT II.

[Neuroimmunoregulatory properties of short protein fragments in rats exposed to immobilization stress]. / Neiroimmunoreguliruiushchie svoistva korotkikh fragmentov belkov v usloviiakh immobilizatsionnogo stressa u krys.

The influence of short protein fragments on immobilization stress-induced alterations in neuroendocrine and immune systems (catecholamine content in the striatum, hypothalamus and adrenals, serum corticosterone concentration, specific antibody producing activity) was investigated. Immunoglobulin G fragments--tuftsin, rigin, polar amino acid set--polarin and thymus hormone fragment--thymopoetin, as well as substance P (as reference drug) were administered intraperitoneally at doses of 100 and 500 micrograms/kg 30 min before exposure to stress. Rigin and thymopentin showed high stress-protective activity. It is suggested that similar protein fragments, being endogenously formed, may play a regulating role in neuroimmunological homeostasis during exposure to stress.

[Characteristics of the neuromodulating effect of peripherally administered thyroliberin on the rat brain]. / Osobennosti neiromoduliruiushchego deistviia perifericheski vvedennogo tiroliberina v strukturakh mozga krysy.

The study of TRH effect on monoaminergic processes (MP) in the rat brain areas (hypothalamus, striopallidar system, cortex) was carried out upon intramuscular administration of TRH in doses of 1, 5 and 10 mg/kg 0.5, 1 and 3 h after TRH injections the animals were decapitated. TRH was shown to elicit persisting (3 h) multidirectional MP alterations in catecholaminergic system and unidirectional alterations in serotoninergic system (mainly acceleration of serotonin turnover). The most marked influence is produced by the lowest TRH dose, 1 mg/kg. It is suggested that in spite of a short half-life (2-5 min) TRH is able to act as a modulator on different target points of the rat MP pathways. That could be one of the possible explanations of previously observed prolonged TRH-induced pharmacological and clinical effects.

[Central action of melanostatin and the opiate system of the brain]. / Tsentral'noe deistvie melanostatina i opiatnaia sistema mozga.

The effects of intraventricular administration of melanostatin (MIF--I, Pro--Ley--Gly--NH2) on the behaviour and electrical activity in neocortex, amygdala, hippocampus and hypothalamus involved an enhancement of electrical activity: MIF enhanced the 3--7/sec high--voltage activity of neocortex, amygdala, hippocampus and the 7--12/sec one of neocortex. Morphine facilitated the effects of MIF whereas preliminary administration of MIF blocked the effect of threshold doses of morphine. After lesion of the central nucleus of amygdala the responsiveness of ipsilateral neocortex disappeared whereas that of hippocampus preserved.

[Mechanism of action of cyclokinins]. / O mekhanizme deistviia tsiklokininov.

Cyclic analogs of bradykinin (CBK) and kallidin (CK) have a weak myotropic activity and a marked and prolonged hypotensive effect unlike linear bradykinin (BK) and kallidin (K) which produce a short-term hypotension and considerable contraction of rat uterus smooth muscles. Myotropic effects of BK and CK were significantly inhibited by phentolamine, methysergide, papaverine and verapamil. Atropine, diphenhydramine and propranolol have no influence on the kinin-induced myotropic responses. The prolonged decrease in blood pressure induced by CBK and CK is observed in un- and anesthetized normotensive, spontaneously hypertensive rats and rats with renovascular hypertension and is absent from anesthetized cats and guinea-pigs. This indicates the species specificity of cyclokinins. Indomethacin, diphenhydramine and methysergide failed to influence the BK- and CK-induced hypotensive effects on anesthetized rats. CaCl2 did not influence the magnitude of the hypotensive effect of BK and CK, however, it significantly shortened the duration of the CK-induced hypotensive effect. In vitro CBK and CK inhibited activity of kininase II in a similar manner (at a concentration range of 10(-5) M) but to a less extent than BK (10(-7)-10(-6) M). It is suggested that the hypotensive effect of CK is mediated at least partly via Ca2+-dependent systems and inhibition of kininase II.

[Comparison of the neuro- and immunomodulator properties of low-molecular neuropeptides]. / Sopostavlenie neiro- i immunomoduliatornykh svoistv nizkomolekuliarnykh neiropeptidov.

A study was made of the effect of the low-molecular neuropeptides, leu- and met-enkephalins, thyroliberin (TRH), the C-end tripeptides, gastrin (MAF) and oxytocin (MIF) on the content of biogenic monoamines and their metabolites and on the production of humoral antibodies to sheep red blood cells. The action of the peptides enumerated was compared to that of the peptide immunostimulant, tuftsin. All the peptides (upon intraventricular administration) with the exception of tuftsin affect the content of brain biogenic monoamines or their metabolites. Moreover, upon intravenous injection the neuropeptides under study except met-enkephalin exert a modulating action on the immune response pattern and intensity Leu-enkephalin, MIF and MAF have immunostimulant activity similar to tuftsin. TRH given in high doses (100 and 150 mg/kg) provokes almost a two-fold decrease in the antibody titer. This peptide has an immunosuppressant effect when administered both intravenously and intracisternally. It is suggested that neuro- and immunomodulator effects have much in common at the level of cell receptors.

[Comparative study of substance P and its fragments: analgesic properties, effect on behavior and monoaminergic processes]. / Sravnitel'noe izuchenie veshchestva P i ego fragmentov: anal'geticheskie svoistva, vliianie na povedenie i monoaminergicheskie protsessy.

The effect of substance P (SP) and of its fragments 5-11, 8-11, 9-11, 10-11 administered into the brain ventricles in doses of 5, 25 and 50 nM on the behavior and content of biogenic monoamines of the rat brain was studied. The analgetic properties of the substances under consideration and those of fragment SP 10-11 in doses of 5, 25, 50 and 100 nM were also subjected to examination. It was found that SP and fragment 5-11 stimulate and enhance the locomotor activity in rats, while fragments 8-11 and 9-11 provoke hypoactivity. The substances under study increase the serotonin and dopamine turnover, whereas SP and fragment 8-11 lower the serotonin content as well. After administration of SP and fragment 5-11 analgesia was seen to transform to hyperalgesia depending on the dose. Fragments 8-11 and 9-11 produce analgetic effect. It is suggested that both SP fragments and the whole SP molecule can influence the neurochemical process that regulate behavior and pain perception.