[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.

The effects of methylxanthines, ethymizol, ephedrine and papaverine on guinea pig and dog trachea.

The study was aimed to compare the effects of pentoxyphylline, aminophylline, choline theophyllinate and ethymizol on guinea pig and dog trachea with those of theophylline, papaverine and ephedrine. The effects of these drugs on the basal tension, on dose-response curves for muscle contraction produced by histamine and on cAMP level were investigated in guinea pig trachea, together with their influence on the resting and histamine-evoked mechanical and membrane activities of dog trachea. Like papaverine, pentoxyphylline did not alter the resting membrane potential, although it relaxed both tracheal preparations, and it antagonised the effects histamine and raised the cAMP level of the smooth muscle. The effects of ethymizol were similar to those of theophylline and its water soluble derivatives (aminophylline and choline theophyllinate). Whereas, ephedrine although it decreased the basal tension and inhibited histamine-evoked responses, also elicited substantial hyperpolarization of the smooth muscle membrane with no effect on the cAMP level. These findings are consistent with the hypothesis that cAMP has an important role in the action of some bronchodilator drugs; however, it is concluded that the possibility of contributing of their action on membrane potential to their action needs to be considered. The similarity of the potencies of ethymizol and pentoxyphylline to that of classical bronchodilators in inhibiting contraction of guinea pig and dog tracheal smooth muscle suggests that they may have a therapeutic value.

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.

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.

[Effect of etimizol on the ultrastructure of the dorsal hippocampus and autonomic ganglia of the rat heart]. / Vliianie étimizola na ul'trastrukturu dorsal'nogo gippokampa i vegetativnykh gangliev serdtsa krys.

The injection of aethimizol to rats (10 mg/kg) causes an irregular widening of cisternae of the granular endoplasmic reticulum in "light" pyramidal neurons of zone CA1 of dorsal hippocampus, which is considered as a depression of the neuronal apparatus of protein synthesis. A 1 mg/kg dose causes, in some synapses, a complex of changes supposed to express the activation of synapses. No essential changes were revealed in the heart neurons. Aethimizol acts selectively on the ultrastructure of central nervous system and does not exert a pronounced action on autonomic neurons.

[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.

[Effect of etimizol on super-slow electrical oscillations and the concentration of noradrenaline in nuclei of the rabbit hypothalamus]. / Vliianie étimizola na sverkhmedlennye élektricheskie kolebaniia i soderzhanie noradrenalina v iadrakh gipotalamusa krolika

Following intramuscular administration of a 2.5 mg/kg dose of ethymisol to curarized rabbits with implanted gold electrodes in the anterior group of hypothalamic nuclei, a correlation was revelaed between the amplitude of superslow electrical oscillations of 0 to 1 c/s and the noradrenaline content in the brain tissue. After ethymisol administration, the positive wave of the slow oscillation disappeared, while the adrenaline content in the hypothalamic area decreased from 0.93 mkg/g to 0.16 mkg/g of the tissue. By means of phentolamine and propranolol adrenoblockators the participation of alpha-and beta-receptors of the hypothalamus in the ethymisol effect has been proved.

[Effect of ethymisole on long-term memory]. / O vliianii étimizola na dolgovremennuiu pamiat'.

Influence of ethymisol (bismethylamid of 1-ethylimidasol-4,5-dicarbonic acid) on learning and retention of habit was studied in experiments on rats by the method of active conditioned avoidance of electrical stimulation. At the same time optimal conformation form of the drug was determined by the method of proton magnetic resonance and by means of infrared spectra and theoretical conformation analysis. A single administration of ethymisol in the dose of 3 mg/kg reduced the deficit of the avoidance habit, when tested in 30 and 60 days following learning. A stable conformation of the ethymisol molecule with a planar arrangement of atoms of its heterocycle and amide groups was found in which the interaction of this substance with biological macromolecules was most active. The ethymisol effect on the long-term memory apparently results from a stable facilitation of synaptic transmission based on stabilization of spatial structure of biological macromolecules in the given conformation.

[Effect of etimizol on behavioral responses, brain serotonin concentration and plasma corticosteroid levels]. / Deistvie étimizola na povedencheskie reaktsii, soderzhanie serotonina v mozge i kortikosteroidov v plazme krovi.

The influence of ethymisol on behavioural reactions was studied on 100 albino rats in the "open field" and "passive avoidance" tests. It was shown that a 5 mg/kg dose of this neurotropic drug with synaptic effect, changes behavioural reactions, lowers the general emotional stress and emotional memory of the electro-cutaneous stimulation. Simultaneously the level of corticosteroids in the blood plasma significantly rises, while the serotonin content in the hypothalamus decreases. A direct correlation between the changes in the emotional stress and the content of corticosteroids in blood plasma is noted. The effects of ethymisol partially persists after adrenalectomy. Ethymisol in optimal doses may be used for regulation and lowering of emotional stress.

[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 effect of etimizol on the excitability and spontaneous super-slow activity of the structures of the rabbit brain]. / Vliianie étimizola na vozbudimost' i spontannuiu sverklmedlennuiu aktivnost' struktur mozga krolika

Spontaneous superslow electrical brain activity and its changes were studied in acute experiments on curarized rabbits after administration of etimysol in doses of 1.0, 1.5 and 2.5 mg/kg. The effect of the drug persisted for three hours. Two oscillation phases were recorded in the medial group of mesencephalic reticular nuclei and the lateral nucleus of the hypothalamus: a short positive phase and a prolonged negative one. In other brain structures only negative waves were recorded. A significant functional rearrangement of correlative connections of brain structures took place in 90 minutes after the drug administration. The factor analysis showed that the most subtle connections were preserved in the neocortex and the dorsal hippocampus.

[Characteristics of the super-slow electrical activity of the brain when exposed to the action of neurotropic substances altering short-term memory]. / Kharakteristika sverkhmedlennoi élektricheskoi aktivnosti mozga pri deistvii neirotropnykh veshchestv, meniaiushchikh kratkosrochnuiu pamiat'

Superslow electrical activity was studied after the action of neurotropic drugs on curarized rabbits with gold electrodes implanted in the deep brain structures. Intramuscular administration of 1/5 mg/kg dose of ethimizol, of 5 mg/kg of ethipyrol, or of 1/5 mg/kg of metamizyl led to a reciprocity of the oscillation amplitudes between the field CA-3 of the dorsal hippocampus and the medial nuclear groups of the reticular formation. Ethimizol and ethipyrol, though producing a similar final effect, act differently on the duration and phases of slow oscillations. Micropolarization of the dorsal hippocampus field CA-3 with a 2.5 microampere current lengthened the action of the neurotropic drugs, up to six hours in the case of ethimyzol. A mathematical vector analysis has shown that the angle of the wave amplitude vector in space depends both on the characteristics of the neurotropic drug and the excitability level of field CA-3 of the dorsl hippo-campus. A slow electrical potential reflecting the capacity of the electric field of a brain structure is likely to be one the major components controlling the conformation position of the receptor proteins.

[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.

[Effect of etimizol on the nystagmic reactions in optokinetic stimulation and aftereffect]. / Vliianie étimizola na nistagmennye reaktsii v period optokineti-cheskoi stimuliatsii i v posledeistvii.

In chronic experiments on rabbits, changes of frequency and amplitude of the optokinetic nystagmus (OKN) were studied during continuous 60-min optokinetic (OK) stimulation and in secondary trace reverse phase of the OKN called the reverse postoptokinetic nystagmus (RPN) for 30 min after cessation of the OK-stimulation prior to and after administration of 5 mg/kg aethimizol. The drug was administered 20 min prior to the OK-stimulation and on the 35th min of the stimulation. Aethimizol was found to increase considerably the OKN frequency, amplitude and the RPN. The RPN frequency was considerably decreased after aethimizol administration. Aethimizol seems to improve the process of nystagmus formation during the OK-stimulation and to weaken the process of formation of the asymmetry of nervous centers excitation during a prolonged OK-stimulation.

[Stationary exitation according to A.A. Ukhtomskii and its role in the mechanism of completion of temporary connections]. / Statsionarnoe vozbuzhdenie po A.A. Ukhtomskomu, i ego rol' v mekhanizme zamykaniia vremennoi sviazi

When recording potentials form the cortical surface, an increase in the processes of local excitation was shown to occur at the moment of revealing the first signs of the conditioned reflex: appearing of slow waves, increasing amplitude of evoked potentials, negative shift of the cortical steady potential. When recording evoked potentials from deep cortical layers, successive stages of transition of the local excitation into a spread one which carries out the conditioning, were shown. Stationary depolarization occurring in conditioning and revealed in gross forms as slow waves, increasing amplitude of evoked potentials, and negative shift of steady potential, at the cellular level is revealed as formation of neuron's polysensory acitvity and is usually followed by increase in the action potential (AP) duration in neurons of the cortical ends of analysers participating in conditioning. Etimizol is known to improve memory processes in man and in animals (2). When acting on the mollusk neurons, etimizol increases AP duration by 144 plus or minus 64 percent. The data obtained suggest that the observed in conditioning increase of AP durration of neurons in the cortical representation of conditioned and unconditioned stimuli is associated with alterations in ion exchange and with trace processes in neurons, which apparently is related to the fine mechanisms underlying the retention in memory.

[Comparison of superslow activity with changes in the function of the neocortical cytostructures]. / Sopostavlenie sverkhmedlennoi aktivnosti s izmeneniiami funktsional'nogo sostoianiia tsitostruktur neokorteksa.

Effects of ethimizole on the infraslow ascillations of the brain electrical activity were correlated with the pattern of its distribution within cellular structures. A negative wave of the infraslow activity was found to occur after the drug administration at the moment of its maximal inclusion into the two cellular fractions: the nuclei and the surface proteins of the endoplasmatic net. These structures seem to play part in changes of the central nervous system's functional state.

[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.

[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.

[Effect of etimizol, ethyrasol, and caffeine on the electrical activity of mollusk neurons]. / Vliianie étimizola, étirazola i kofeina na élektricheskuiu aktivnost' neironov molliuskov.

In experiments on Limnae stagnalis neurons, ethymisol increased the AP duration while reducing the trace hyperpolarization and the rate of development of the AP descending phase. Ethymisol (10 mM/1) induced either hyperpolarization of neurons with an increase in membrane resistance or their depolarization (20 mM/1) with a decrease in membrane resistance. A drop in the medium temperature by 2-4 degrees C prevented the hyperpolarization. The ethymisol-induced hyperpolarization seems to be connected with a decrease in membrane permeability for sodium ions in resting conditions and with activation of electrogenic ion transport. The increase of extraneuronal potassium up to 4 mM/1 and depolarization induced by currents of 1-3 nA intensified the ethymisol effects. Ethymisol decreased efflux and influx of ions through membrane thus affecting the AP parameters. The effects of ethymisol also involved an increase of neurons excitability and intensification of synaptic activity. Neither ethyrasol nor caffein exerted these effects.