[Effect of etimizole structural analogues on protein kinase CK2, protein phosphorylation and transcription of chromatin in rat brain cortex and hippocampus]. / Vliianie strukturnykh analogov étimizola na proteinkinazu SK2, fosforilirovanie belkov i transkriptsiiu khromatina neironov kory i gippokampa mozga krys.

Protein kinase CK2 is an important enzyme in the nervous system. The nuclear forms of CK2 regulate chromatin structure and gene expression, the key processes for long-term memory formation. Memory modulators, the Structural Analogues of Etimizole (SAE), were able to increase or decrease the activity of chromatin-associated CK in the cortex and hippocampus of rat brain in vitro. In vivo memory enhancers from SAE-group (3 mg/kg) stimulated CK2 activity and the transcriptional ability of chromatin in the cortex and hippocampus, starting from 30 min with a peak for 60 min and a duration up to 180 min. At these periods the memory inhibitor from the SAE-group reduced CK2 activity and chromatin transcription. It is assumed that the modulating effect of SAE on CK2 activity and transcription underlies the effects of these compounds on long-term memory.

Status of the "protein kinase CK2-HMG14" system in age-related amnesia in rats.

The experiments described here demonstrate that disruption of the phosphorylation of transcription factors of the HMG cAMP/Ca-independent protein kinase CK2 class may be the cause of decreased gene expression in age-related cognitive deficits. Amnesia for a conditioned passive avoidance reaction (CPAR) in aged rats (24 months old) was accompanied by decreases in the synthesis of synaptosomal proteins and transcription in nuclei isolated from cortical, hippocampal, and striatal neurons. There was a decrease in chromatin protein kinase CK2 activity and a significant decrease in the phosphorylation of HMG14 by protein kinase CK2. Selective activators of protein kinase CK2 (1-ethyl-4-carbamoyl-5-methylcarbamoylimidazole and 1-ethyl-4,5-dicarbamoylimidazole) increased HMG14 phosphorylation by protein kinase CK2, increased transcription, increased the synthesis of synaptosomal proteins, and decreased amnesia for the CPAR in aged rats. Thus, activation of the "protein kinase CK2-HMG14" system is accompanied by optimization of synaptic plasticity in aged animals. The results provide evidence for the high therapeutic potential of protein kinase CK2 activators.

Formation of didesmethylethimizol (4-5-dicarbamoyl-1-ethylimidazole) in man.

The chemical structure of an ethimizol metabolite found earlier in human urine and saliva was established as 4,5-dicarbamoyl-1-ethylimidazole (didesmethylethimizol). The treatment of biological samples comprised a solid-phase extraction, high-performance thin-layer chromatographic separation and high-performance liquid chromatographic purification techniques. The identification of the metabolite was based on the comparison of a mass spectrum of the substance isolated from the biological fluid with the mass spectra of synthetised reference compounds.

[The embryo-protective action of antifein derivatives in chloridin-induced teratogenesis]. / Embrioprotektivnoe deistvie proizvodnykh antifeina pri khoridinindutsiruemom teratogeneze.

We studied the effect of propyl- and ethylnorantifein on chloridine-induced abnormalities of extremities in rat embryos. Chloridine (50 and 25 mg/kg, given through the gastric tube) was administered to rats on day 14 of pregnancy, and its embryotoxic effect was estimated from the state of fetuses and implantation sites on day 20 of prenatal development. Propylnorantifein had fetoprotective properties both after intraperitoneal (10 mg/kg) and after intraamniotic (6 and 0.06 micrograms) administration. Ethylnorantifein under similar conditions does not change the action of chloridine, and it prevents the appearance of developmental abnormalities only at the concentration of 0.06 microgram/embryo. These data are discussed in connection with different effects of antifein derivatives on chromatin proteinkinase, which phosphorylates HMG nonhistone proteins.

[The participation of RNA synthesis in the process of the acquisition and retention of conditioned reflexes (a study using antifeins)]. / Uchastie sinteza RNK v protsesse vyrabotki i sokhraneniia uslovnykh refleksov (issledovanie s ispol'zovaniem antifeinov).

RNA-synthesizing activity of neuronal nuclei in the neocortex of rats increases after the termination of conditioning depending on the degree of learning. RNA synthesis shifts induced by propylnorantifein and the demethylated derivatives of ethylnorantifein are correlated only with the influence of the drugs on the retention but not the learning. Participation of RNA synthesis by the neurons of the neocortex in the mechanisms of long-term memory is discussed.

[The participation of the genetic apparatus in the mechanisms of memory trace formation: the role of the calcium-regulatory system of the neurons in rats]. / Uchastie geneticheskogo apparata v mekhanizmakh sledoobrazovaniia: rol' kal'tsii-reguliatornoi sistemy neironov krys.

The dynamics of changes in some components of the calcium-regulated system of cortical and hippocampal neurons under the influence of long-term memory enhancers (ethylnorantifein and its analogues M1 and M2) was studied in rat brain. No change was found in the activity of transport Mg, Ca-ATPase and actomyosin-like Ca-ATPase in synaptic membranes 5, 15, 60, and 180 min after the injection of memory enhancers. The activation of the RNA transcription (60 min after the injection) was accompanied by an appreciable increase in activity of the chromatin Ca-ATPase. The amplification of synaptosomal protein synthesis (180 min) was accompanied by an increase in the activation of protein kinase C of synaptic membranes. The increase in Ca-ATPase activity of chromatin was also shown during the consolidation of the conditioned active avoidance in rats. The increase in the activity of protein kinase C seems to be connected with secondary rearrangement in synaptic membranes. The role in the long-term memory is discussed of direct activation of the genetic apparatus by neuroactive substances.

[Interhemispheric relation of brain structures in various functional states of the central nervous system]. / Mezhpolusharnye vzaimootnosheniia struktur mozga pri raznykh funktsional'nykh sostoianiiakh tsentral'noi nervnoi sistemy.

In rabbits with indwelled gold electrodes, multiminute oscillations of infraslow activity were recorded within the range from 0 to 1 Hz. The temperature of cerebral structures was recorded from symmetrical areas with the aid of thermocouple. Changes of the functional state were induced by means of 1) unilateral microstimulation of frontal neocortex with 1.5-2.5 microA; 2) administration of neurotropic activators: aethimizole and its analogue: and 3) prolonged administration of ethanole. All these influences sharply increased the natural functional interhemisphere assymmetry inducting a rearrangement of intracentral interrelationships. Use of the neurotropic activators (aethimizole and IEM-476) temporarily restored the normal interaction between the cerebral hemispheres even if the functional interhemisphere asymmetry was still obvious.

[Dynamics of 1-minute superslow oscillations during the process of formation of a shortened reflex]. / Dinamika minutnykh sverkhmedlennykh kolebanii v protsesse formirovaniia ukorochennogo refleksa.

Formation of encephalogenic shortened reflex in rabbits induced specific local changes of amplitudes of the 1-min waves. Etimizol rapidly stabilized the level of the 1-min waves and fixed the reflex, keeping the local character of the response. Propylnorantiphein enhanced corticofugal projections to the thalamus. The shifts in the brain energy exchange (the creatin--phosphate, glycogen contents) coincided in time with the amplitude shifts of the 1-min waves and occurred within 20--30 min after administration of neurotropic drugs lasting 2--3 hrs. The etimizol recruited both alpha-and beta-adrenoreceptors whereas the propylnorantiphein involved mainly the alpha-adrenoreceptors. Etimizol, being an unspecific connector, enhanced consolidation of the shortened reflex increasing the local response to electric stimulation, whereas propylnorantiphein aided to spreading of the responses over to the thalamic nuclei.

[The effect of structural analogs of ethylnorantifeine on the autophosphorylation of cAMP-independent protein kinases of neuronal chromatin]. / Vliianie strukturnykh analogov étilnorantifeina na autofosforilirovanie tsAMF-nezavisimykh proteinkinaz khromatina neironov.

A significant increase in autophosphorylation of cAMP-independent protein kinase No. 11 of brain neuronal chromatin occurs in the presence of ethylnorantifeine and its demethylated analog M1 rather than allyl- and propylnorantifeine. The increase is accompanied by phosphorylation of beta-regulatory and alpha-catalytic subunits of protein kinase No. 11. The nature of the direct action of antifeines on this enzyme correlates with their effects on gene activity and long-term memory storage. Whether neuronal chromatin protein kinase No. 11 is the action target of antifeines in displaying their mnemic effects is discussed in the paper.

Demethylation in vivo of a xanthine-related respiratory analeptic, ethimizol.

Demethylation of ethimizol in humans yielded 1-ethyl-4-carbamoyl-5-methyl-carbamoylimidazole. The formation, and the excretion in urine or saliva, of the other mono-N-demethylated ethimizol isomer, 1-ethyl-5-carbamoyl-4-methylcarbamoylimidazole has not been detected.

[Characteristics of the ultraslow activity and temperature of the brain as affected by neurotropic substances]. / Kharakteristika sverkhmedlennoi aktivnosti i temperatury mozga pri deistvii neirotropnykh veshchestv.

It has been demonstrated in experiments on rabbits with golden electrodes and thermocouples implanted to the brain that ethimizol (1.5 mg/kg) and 1-ethyl-4,5-di-(N.-methylcarbamoyl)-pyrazole (IEM-476, 3 mg/kg) altered the amplitude and frequency of ultraslow wave potentials and decreased the temperature of the hypothalamus, dorsal hippocamp and neocortex. Allylnorantifein (1-allyl-4,5-di-(N-methylcarbamoyl)-imidazole, 3 mg/kg) and 1-allyl-4,5-di-(N-methylcarbamoyl)-pyrazole (IEM-474, 3 mg/kg) altered the amplitude and frequency of ultraslow wave potentials of middle brain reticular formation nuclei, medial thalamic nuclei and of the neocortex, the structures of the nonspecific ascending system of the brain, and did not influence the temperature of the brain. The effects of IEM-476 and IEM-474 on the indicators under study were less powerful than those of ethimizol and allylnortifein.

[Effects of antifeins with different memory effects on cAMP phosphodiesterase, lipid peroxidation and RNA synthesis in rat brain neurons]. / Vliianie antifeinov s razlichnymi mnesticheskimi éffektami na fosfodiésterazy tsAMF, perekisnoe okislenie lipidov i sintez RNK v neironakh golovnogo mozga krys.

It has been shown that ethylnorantifein and its structural analogues with opposite effects on long term memory reduce the activity of membrane bound phosphodiesterase cAMP with high and low affinity and exert the same directed influence on lipids peroxidation in membranes. A positive correlation was observed only between the action of these substances on the long term memory and their influence on the RNA synthesis in the rat brain nuclei. Ethylnorantifein and its demethylated analogues increased RNA synthesizing activity while allyl- and propylnorantifeins decreased it. The molecular mechanisms of memory effects of neuroactive substances are discussed.

[Antiamnestic properties of pyrazole dicarboxylic acid derivatives in rats]. / Izuchenie antiamnesticheskikh svoistv proizvodnykh pirazoldikarbonovoi kisloty u krys.

Eight derivatives of pyrazole dicarboxylic acid (IEM-565, IEM-476, IEM-1332, IEM-474, IEM-373, IEM-440, IEM-1333, IEM-439) have been studied in rats for the ability to abolish the amnesia of passive avoidance behavior induced by electroconvulsive shock IEM-476, IEM-373 and IEM-439 have proved to be the most efficacious.

[Effect of etimizol and propylnorantifein on myocardial respiratory enzymatic activity in a neurogenic lesion]. / Vliianie etimizol i propilnorantifeina na aktivnost' dykhatel'nykh fermentov miokarda pri ego neirogennom porazhenii.

Studies on rabbits have shown that neurogenic injury to the myocardium induced by 3-hour electric stimulation of the aortic arch resulted in considerable changes in the activity of respiratory enzymes such as succinate dehydrogenase and cytochrome oxidase. Premedication of the animals with ethymisole and propylnorantipheine that stimulate energy metabolism in the central nervous system of animals has a protective action on the myocardial enzymes tested.

[Animal behavioral reactions, adrenocortical activity and brain energy metabolism under the action of propylnorantifein]. / Povedencheskie reaktsii, adrenokortikal'naia aktivnost' i énergeticheskii obmen golovnogo mozga zhivotnykh pri deistvii propilnorantifeina.

Behavioral reactions induced in white rats by propylnorantifein were studied by the tests of an open field, passive avoidance and self-stimulation from the medial bundle of the fore brain and Raffe suture. Biochemical analysis was done on the content of corticosteroids in blood plasma and that of glycogen and creatine phosphate in brain tissue. Propylantifein in a dose of 5 mg/kg was shown to decrease the self-stimulation, to change the emotional memory in response to pain stimulation, to increase the concentration of corticosteroids in blood plasma. During 3 hr after the drug administration brain tissue demonstrated the decreased glycogen content and particular, drastically reduced the drug action. It is suggested that propylantifein may activate the adenylcyclase system in brain tissue.

[State of the "protein kinase CK2-HMG14" system in age-dependent amnesia in rats]. / Sostoianie sistemy "proteinkinaza CK2-HMG14" pri vozrastnoi amnezii u krys.

It has been shown that a decrease in HMGs transcription factors phosphorylation by protein kinase CK2 may be the cause of a gene expression decline in cognitive disorders. Passive avoidance amnesia in old rats (24 month) was accompanied by a decrease in synaptosomal protein synthesis and transcription in isolated nuclei of cortex, hippocampus, and striatum. A decrease in chromatin protein kinase CK2 activity and a significant decrease in HMG14 phosphorylation by CK2 was found in old rats. CK2 selective activators, a 4-carbamoyl-5-N-methylcarbamoyl-1-ethyl-imidazole and 4,5-dicaramoyl-1-ethyl-imidazole, produced the HMG14 phosphorylation and transcription activation in old rats. At the same time, synaptosomal protein synthesis activation and passive avoidance amnesia reduction were observed in old rats. Thus, activation of CK2-HMG14 was accompanied by synaptic plasticity optimisation. The data show a high therapeutic potential of activators of CK2-HMG14.