[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.

[Ethymisole: reassessing and old drug].

Ethymisole, or 4,5-di(N-methylcarbamoyl)-1-ethyl-imidazole, is a cognitive enhancer and nootropic drug, the molecular target of which is a multifunctional protein kinase C K2 (casein kinase II). New data about signal pathways and protein substrates of CK2 have been obtained due to research effort of many laboratories. The paper presents a historical sketch of molecular investigations underlying memory enhancer effects of ethymisole; this and the other pharmacological effects of ethymisole are considered in the light of new data.

[Ethimizol impact on the fatigue of the inspiratory muscles]. / Vliianie étimizola na utomlenie inspiratornoi dykhatel'noi muskulatury.

The aim of the study was assessment of ethimizol effects on fatigue of respiratory muscles and ventilatory disorders caused by inspiratory resistive load on respiration. Cat experiments showed that administration of ethimizol in inspiratory fatigue reestablishes total bioelectric activity of the inspiratory muscles and diaphragmatic nerve, diminishes useful respiratory cycle and respiration rate. Thus, ethimizol in a 1 mg/kg dose i.v. compensates inspiratory muscular fatigue via central mechanism of action.

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.

[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.

[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.

The effect of cytochromes P4501A induction and inhibition on the disposition of the cognition activator tacrine in rat hepatic preparations.

1. The disposition of tacrine 1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate (THA, Cognex), was studied using livers obtained from control, phenobarbital (PB), isosafrole (ISO), and 3-methycholanthrene (3-MC) treated rats. 2. Pretreatment of rats with PB, ISO, and 3-MC reduced AUC(10-120 min) of THA in liver perfusates by 28, 32, and 86% respectively. 3. Elimination of [14C]-THA-derived radioactivity into bile was 7.6 +/- 1.2%, 11.7 +/- 2.9%, 14.8 +/- 2.0%, and 46.3 +/- 9.7% (mean +/- SD) of the infusion dose for control PB, ISO, and 3-MC pretreated isolated perfused rat livers, respectively. 4. In perfusion experiments using 3-MC pretreated livers, a marked increase in irreversible protein binding of 3-, 7-, and 8-fold was observed to microsomal, cytosolic and total liver proteins, respectively, compared to control. Only a slight effect was observed on protein binding in perfusion experiments using PB and ISO pretreated animals. 5. Co-incubations of [14C]-THA with the metabolic inhibitors enoxacin, ethimizol, and furafylline in hepatocyte preparations obtained from 3-MC pretreated rats markedly inhibited THA-derived irreversible protein binding. Furafylline, a specific inhibitor of cytochrome P4501A2, had the greatest inhibitory effect (approximately 70%). 6. These results are consistent with a major role of cytochrome P4501A in the metabolism and irreversible protein binding of THA in rat liver and demonstrate the utility of isolated liver perfusion and hepatocyte models for examining the effect of metabolic modulators.

[The effect of etimizol on the functional status of the blood coagulation systems and fibrinolysis in workers on expedition-duty watches working under the climatic conditions of northern Tyumen Province]. / Vliianie étimizola na funktsional'noe sostoianie sistem gemokoaguliatsii i fibrinoliza u rabochikh ékspeditsionno-vakhtovykh brigad, rabotaiushchikh v klimaticheskikh usloviiakh Tiumenskogo Severa.

The study was undertaken to reveal the effects of ethymisole on the functional status of blood coagulation and fibrinolytic systems, the body's adaptative reserves of workers from expeditionary-duty teams. Ethymisole was found to normalize the functional status of blood coagulation and fibrinolytic systems, to restore conjunction of their functioning. The use of the drug was ascertained to normalize the activity of lipid peroxidation products, to enhance the adaptative reserves of expeditionary-duty workers by prolonging the resistance phase. It is concluded that ethymisole may be used as an agent that enhances the body's adaptative reserves.

[The effect of neuroleptics on blood proteins during development of toxic cerebral edema-brain swelling]. / Vliianie neiroleptikov na sistemu belkov krovi pri formirovanii toksicheskogo oteka-nabukhaniia golovnogo mozga.

Simulation of toxic brain edema-swelling allowed one to analyze the dynamics of blood protein alteration in presence of various neuroleptics. Alterations in blood protein fractions correlated with dynamics of nervous tissue impairments. All the drugs studied exhibited similar antiswelling action involving the gamma-globulin sub-system activation. At the same time, the neuroleptics with activating and depriving effects demonstrated an oppositely directed influence on blood albumins.

Participation of RNA synthesis in the process of the development and maintenance of conditioned reflexes (an investigation using antitheines).

It has been established that an increase in RNA synthesis in the neurons of the cerebral cortex of rats at the stage of consolidation is manifested in well-trained animals more strongly than in poorly trained animals. The selective influence of propylnorantitheine and demethylated derivatives of ethylnorantitheine on the maintenance of conditioned reflexes has been demonstrated. The effects of these substances on consolidation and long-term memory correlate with the change in the RNA-synthesizing activity of neurons during the effect both in systemic experiments and with the direct interaction with the chromatin of the neurons. The participation of the RNA synthesis of cerebral cortical neurons in the mechanisms of long-term memory is discussed.

[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.

[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.

[Effect of HMG proteins and their phosphorylated forms on the process of transcription in neuronal nuclei of the rat brain (data from an immunochemical analysis)]. / Vliianie belkov HMG i ikh fosforilirovannykh form na protsess transkriptsii i neironal'nykh iadrakh golovnogo mozga krys (dannye immunokhimicheskogo analiza)

It was found that chromatin transcription in the neuronal nucleus of rat brain is inhibited by antisera to proteins HMG 14, HMG 17 and HMG 2. It is known that chromatin transcription of the neuronal nucleus and phosphorylation of chromosomal proteins are activated by etimizol. The phosphorylation of chromosomal proteins activated by etimizol is inhibited by the antiserum to HMG 14 (but not to HMG 17). The data obtained are suggestive of a possible role of HMG proteins and their phosphorylated forms in the regulation of transcription.

[Current aspects of the search of effective nootropic drugs]. / Sovremennye aspekty poiska éffektivnykh nootropnykh sredstv.

The authors review different mechanisms of mnemotropic and cerebroprotective effects of nootropic drugs. The data concerning the molecular mechanisms of action of the structural analogs of the memory stimulant ethylnorantifeine (etimizol) have been summarized and analyzed. It is shown that the effects of antifeines on the retention of the conditioned reflexes are independent of their effects on the cAMP system and structural-functional condition of the neuronal membrane. The key role in the action of these compounds on the long-term memory is played by the activity of the genetic apparatus. The existence of nootropic receptors in neuronal chromatin is assumed.

[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.

[Vasodilating effects of etimizol in vitro and its relation to purinergic receptors]. / Vazodilatacné úcinky etimizolu in vitro a ich vztah k purínergickým receptorom.

The paper is concerned with the effect of the breath analeptic agent etimizole on the smooth muscle of vessels under in vitro conditions from the viewpoint of its assumed interaction with purinergic receptors. Isolated preparations of the coronary artery and a. dorsalis pedis of the dog served as experimental material. Etimizole administered in a cumulative manner in dependence on concentration decreases the strength of contraction of the preparations contracted with K+ ions. This relaxant effect, similarly as the effect of adenosine, is not affected by a removal of the endothelium, can be inhibited with theophylline and potentiated with dipyridamole. Etimizole in higher concentrations inhibits the response of vascular preparations to electrical stimulation. In the concentration of 10(-4) mol.l-1 it potentiates the relaxant effect of adenosine, the experimental effects not differing from the theoretical curve for the addition of effects. The obtained results support the assumption that the vasodilating effect of etimizole is mediated prevalently by P1 purinergic receptors.

[Role of sex dimorphism in the pharmacological action of etimizol]. / Rol' polovogo dimorfizma v farmakologicheskom éffekte étimizola.

It has been shown that in female rats the level of ACTH, corticosterone in the blood, relative mass of adrenals, maintenance of T3, T4 in the serum and liver was significantly higher, but the activity of liver enzyme microsomes system was lower than in males; no sex differences were observed in myocardial creatine phosphokinase system. The influence of the etimizol on the female rats significantly speed up amidopyrine N-demethylation and biotransformation of hexobarbital. In males these systems react less on etimizol, but it reduces the speed of amidopyrine N-demethylation.