Search

The cerebral effects of subeluzole have been studied using the following methods: hypobaric hypoxia in mice, complete ischemia by decapitation in mice, anoxic hypoxia in mice, hemic hypoxia in rats, incomplete ischemia by bilateral carotid ligation in rats, anoxic hypoxia in rats and asphyxic hypoxia in cats. Sabeluzole was active in all the models used: it increased the survival time in hypobaric hypoxia (maximum at 40 mg/kg--by 92.0%, p less than 0.001), survival time in anoxic hypoxia in mice (maximum at 40 mg/kg--by 27.2%, p less than 0.001), gasping in decapitation model (maximum at 20 mg/kg--by 155.4%, p less than 0.001) and survival in hemic hypoxia (maximum at 2.5 mg/kg--by 21.1%, p less than 0.05). The duration of the effect as evaluated in the decapitation model was about 6 h. In incomplete ischemia in rats, however, it showed a weak effect. In anoxic hypoxia in rats, sabeluzole (5 mg/kg i.v.) increased the time latency between onset of anoxia and negative DC-shift by 20.5% and the K+e-threshold by 25.7%. In asphyxic hypoxia in cats, sabeluzole (0.5 mg/kg i.v.) counteracted the hypoxia-induced decrease of the fast-wave amplitudes during the cortical resistance period and the hypoxia-induced decrease of the slow-wave and increase of the fast wave amplitudes during the cortical recovery period.

The effect of flunarizine on the rheoncephalogram (REG) and on spontaneous electroencephalographic activity (EEG) was studied in acute experiments in cats. The following REG parameters were assayed: amplitude, anacrotic section of the curve and its relative part, and dicrotic index. EEG spectra were derived from 10-sec samples of EEG and the relative amplitudes were estimated at 2 Hz-intervals from 0-40 Hz. The REG study showed that flunarizine (2.5 and 5 mg/kg i.v.) caused an increase of the amplitude and a decrease of the anacrote, of its relative part, and the dicrotic index, changes indicating a lowering of the cerebrovascular resistance. EEG study showed a decrease of the amplitudes of the alpha-frequency band, and an increase of the fast-waves amplitudes, most pronounced at 5 mg/kg, changes showing enhancement of the activation processes in the brain cortex.

The cerebroprotective effect of flunarizine was studied using the following methods: hypobaric hypoxia in mice, complete ischemia by decapitation in mice, anoxic hypoxia in mice, hemic hypoxia in rats, incomplete ischemia by bilateral carotid ligation in rats and asphyxic hypoxia in cats. Piracetam, meclofenoxate, nicergoline, naftidrofuryl, cinnarizine and nifedipine were studied as reference drugs. Flunarizine increased the survival time in all survival models. Its effect was most pronounced in complete ischemia model, and considerably higher than that of reference drugs. In asphyxic hypoxia flunarizine increased cortical resistance and shortened cortical recovery. The EEG frequency-amplitude analysis during asphyxic hypoxia showed a significant decrease of the slow-waves amplitudes of delta and theta range, and an increase of the fast-waves amplitudes of beta-2 range, changes indicating protective action.

The effect of nicergoline on the rheoencephalogram (REG) and on spontaneous electroencephalographic activity (EEG) was studied in acute experiments in cats. The following REG parameters were assayed: amplitude, anacrotic section of the curve and its relative part and dicrotic index. EEG spectra were derived from 10-sec samples of ECoG and the relative amplitude was estimated at 2 Hz-intervals from 0-44 Hz. The REG study showed that nicergoline (0.05 mg/kg i.v.) caused an increase of the amplitude, and a decrease of the anacrote, of the relative part of the anacrote and the dicrotic index - changes indicating a lowering of cerebrovascular resistance. EEG study showed a decrease of the slow activities (theta and delta), and an increase of the fast activities (alpha and beta-1).

The protective effect of piracetam against PGF2 alpha-impaired cerebral resistance to hypoxia was investigated by EEG study in relaxed and artificially ventilated cats. Asphyxic anoxia was performed after 5 min of intracarotid (i.c.) or i.v. infusion of 10 micrograms/kg/min PGF2 alpha before and 30 min after piracetam (100 mg/kg i.v.). The following parameters were determined: cortical resistance (CRs)--as time between stopping the ventilation and the extinction of EEG; cortical recovery (CRc) - as time between restitution of ventilation and reappearance of brain activity; anoxia resistance index (ARI) - as the ratio between these two parameters (CRs/Crc). Both the i.c. and i.v. infusion of PGF2 alpha led to a significant decrease in CRs and lengthening of CRc which resulted in a decrease in ARI. Piracetam reverses the PGF2 alpha-induced changes in asphyxic anoxia. The possible mechanism of piracetam's effect and the probable therapeutic value of the latter are considered.

The antagonistic action of aligeron as compared to that of papaverine against different smooth muscle stimuli was studied in experiments in vitro. Three series of experiments were conducted: study of the antagonistic action against experimental spasms of isolated organs caused by different spasmogens; determination of the type of antagonism to adrenaline in isolated vas deferens preparation; and study of the antagonistic action against vasoconstrictor effects of noradrenaline and adrenaline in isolated perfused rabbit renal artery. Aligeron showed a broad spectrum of antagonistic action against different spasmogens in different isolated organs. Its effect was more pronounced than that of papaverine. The antagonism was of the non-competitive type. The experiments on isolated perfused rabbit artery showed the antagonistic action of aligeron against the vasoconstrictor effects of noradrenaline and adrenaline. The results suggest the clinical use of aligeron in conditions associated with increased release of these vasoactive substances.

In connection with some contradictions in the electroencephalographic data for piracetam, further investigations have been carried out to study its effect on the spontaneous and evoked EEG in intact cats after single and a 10-day administration of the drug. On the basis of analysis of the electroencephalogram using an ISEMA frequency-amplitude analyser, the values of the frequency ranges and those of the mean amplitude were averaged by use of FACOM computer. The results from our experiments indicate that no visual differences in the spontaneous and evoked EEG after piracetam administration have been observed. The spontaneous activity after the 10-day treatment with 1000 mg/kg i.m. quantitatively shows an increase of the fast frequencies (beta and alpha waves), increase of the mean amplitude, and increase of the evoked activity after visual and sound stimulation. An involvement of deep structures in performing the effect of piracetam is admitted as well as kind of "augmentation" of the cerebral bioelectrical activity.

The anti-hypoxic effect of piracetam was studied using the following experimental methods: hypobaric and anoxic hypoxia in mice, complete ischemia by decapitation in mice, incomplete ischemia by bilateral carotid occlusion in rats and hemic hypoxia in rats. Cinnarizine and vinpocetine were used as reference drugs. In hypobaric hypoxia, anoxic hypoxia, and complete ischemia by decapitation the interaction of piracetam with the effect of prostacyclin (PGI2) was investigated. Piracetam showed anti-hypoxic effect in all the methods used. Its effect was greater than that of cinnarizine and similar to that of vinpocetine. Piracetam potentiated the effect of PGI2 shifting the anti-hypoxic dose-response curve of PGI2 to the left.

The effect of piracetam on the excitability of the brain has been examined in cats by electrophysiological approaches: spontaneous electrocorticogram (ECoG), visual evoked potentials (VEPs) and their recovery cycles in some brain structures (visual and associative cortex, lateral geniculate body, centrum medianum thalami and mesencephalic reticular formation). Piracetam (100 mg/kg i.v.) increased the spectral power of ECoG and particularly in the associative cortex for the frequency bands of 10-12 and 19-22 Hz. Piracetam decreased the early components and facilitated the late components of VEPs predominantly in the associative cortex. Changes were found in the recovery cycles too, namely, facilitation and shortening of recovery in all structures studied except in lateral geniculate body. The data suggest that piracetam acts as a non-specific activator on the excitability thus optimizing the functional state of the brain.

Prostacyclin (PGI2) induced a dose-dependent prolongation of survival time of mice subjected to hypoxic and anoxic hypoxia, when administered either intracerebroventricularly (i.c.v., 0.001-10 micrograms/mouse), intravenously (i.v., 0.5-500 micrograms/kg) or intraperitoneally (i.p., 50-500 micrograms/kg). The effects of a single dose of 50 micrograms/kg i.v. or i.p. and of 1 microgram/mouse i.c.v. persisted for about 30 min. The anti-hypoxic effect of PGI2 is most likely due to an action upon the CNS.

The anti-hypoxic effect of cinnarizine was studied using the following experimental methods: hypobaric and anoxic hypoxia in mice, complete ischemia by decapitation in mice and hemic hypoxia in rats. Papaverine, xanthinol nicotinate and naftidrofuryl were used as reference drugs. In hypobaric and anoxic hypoxia the interaction of cinnarizine with the effect of prostacyclin (PGI2) was investigated. Cinnarizine showed an anti-hypoxic effect in all the methods used. It was more effective in hypobaric and anoxic hypoxia, in incomplete ischemia by decapitation, and less effective in hemic hypoxia. Cinnarizine potentiated the effect of PGI2 shifting the anti-hypoxic dose-response curve of PGI2 to the left. Suggestions as to the possible mechanism of anti-hypoxic action of cinnarizine are made.

The effect of Aligeron (1-benzhydril-4-allyl-piperazine dihydrochloride) on the cranial circulation was studied in dogs under chloralose-urethan anaesthesia. The parameters followed were: venous outflow from the confluence of the cerebral sinusses (CVO), cerebrospinal fluid pressure in cysterna magna (CSFP), systemic arterial blood pressure (BP) and pulse rate (PR). CVP was measured using the technique of Rapela and Green (1964). Aligeron was applied at doses of 5 and 10 mg/kg i.v. Papaverine hydrochloride was used as a reference compound. aligeron administration at a dose of 5 mg/kg led to quick increase of the CVO with a duration of the effect approximately 30 min. CSFP also increased in a similar way. BP and PR showed insignificant changes. The administration of 10 mg/kg did not lead to an increase of its effect on CVO. Papaverine (1 mg/kg i.v.) had a weaker effect than that of Aligeron. According to the classical concepts the changes observed in our experiments were due to the cerebral vasodilator effect of Aligeron which caused a fall in cerebrovascular resistance and an increase of the intracranial blood volume. Our experiments suggest that Aligeron influenced the resistance vessels more than the capacitance ones.

The cerebroprotective effect of nicergoline was studied using the following experimental methods: hypobaric and anoxic hypoxia in mice, complete ischemia by decapitation in mice, incomplete ischemia by bilateral carotid ligation in rats, hemic hypoxia in rats and asphyxic anoxia in cats. Xanthinol nicotinate, vincamine, vinpocetine and cinnarizine were used as reference drugs. In hypobaric hypoxia and complete ischemia by decapitation the interaction of nicergoline with the effect of prostacyclin (PGI2) was investigated. Nicergoline showed cerebroprotective effect of varying potency in all the methods used except asphyxic anoxia. Nicergoline manifested a synergic effect with PGI2 shifting its anti-hypoxic dose-response curve to the left.

The effects of a new benzamide derivative LIS-630 and the well-known neuroleptic, tiapride, were studied on stress-induced hyper- and hypoactive emotional behavioral reaction of animals depending on the individual ability for perceptive-cognitive activity in stress situations, and their affinity to striatal DA receptors. A modified variant of forced swimming method was used. The affinity of the substances to striatal DA receptors was studied by the radioligand binding method using 3H-spiroperidol. The results show that the psychopharmacological profile of LIS-630 differs significantly from the neuroleptic, tiapride. LIS-630 restored escape behavior from stress situation after preliminary exposure of rats to forced swimming and did not disturb escape behavior in animals more resistant to emotional hypoactivity. LIS-630 reduced immobility time at forced swimming. However, it is not effective in preventing hyperemotional reactions induced by L-dopa and stress. The radioligand binding study shows that LIS-630 did not displace 3H-spiroperidol from the binding sites of striatum membranes. The parameters of displacement with tiapride were satisfactory.

The anti-hypoxic effect of some agents used in the pharmacotherapy of cerebrovascular disease was studied using the following methods: incomplete ischemia by bilateral carotid ligation in rats, anoxic hypoxia by inhalation of argon in mice, and hemic hypoxia induced by injection of sodium nitrite (120 mg/kg s.c.) in rats. The following drugs were studied: piracetam, orotic acid, centrophenoxine, pentobarbital, vincamine, vinpocetine, cinnarizine, aligeron, xanthinol nicotinate and papaverine. The most pronounced anti-hypoxic effect was shown primarily with the metabolic acting drugs, such as orotic acid, centrophenoxine, piracetam and pentobarbital, followed by the preparations with combined metabolic and vasoactive properties (vincamine and vinpocetine). The predominantly vasoactive drugs were less effective in anoxic hypoxia, but showed more pronounced effect in incomplete ischemia.

The anti-amnestic action of nicergoline was studied using the following experimental methods for learning and memory impairment, based on passive avoidance response: amnesia induced by maximal electroshock in mice, scopolamine-induced amnesia in mice and amnesia by paradoxical sleep deprivation in rats. Piracetam, meclofenoxate, pyritinol, deanol and phenazepam were used as reference drugs. The results show that nicergoline demonstrates well-expressed anti-amnestic effect manifested by reducing the amnestic effect of maximal electroshock, scopolamine or paradoxical sleep deprivation, its effect being equal to or more pronounced than piracetam, meclofenoxate, pyritinol, deanol and phenazepam.

The influence of piracetam (2-oxo-1-pyrrolidine-acetamide, Pyramem) on the cerebral circulation and brain bioelectrical activity of cortex and mesencephalic reticular formation (RF) was studied in acute experiments on cats which were encéphale isolé preparations. The methods of local cerebral rheoencephalography (REG) and electroencephalography (EEG) were used. The following REG parameters were assayed: anacrotic section of the curve and its relative part, amplitude and duration of the wave. The arterial blood pressure was followed continuously. The results show that upon piracetam administration (150 mg/kg i.v.) an improvement of the REG parameters of the cortex and RF is observed-an increase of the amplitude and decrease of the values of the anacrotic section of the curve and its relative part. The changes observed indicate a cerebro-vascular resistance decrease and give indirect evidence of cerebral blood volume increase. EEG data are characterized mainly by an increase of alpha-waves, both of cortex and RF. Suggestions for possible mechanism of action of piracetam are made.

The influence of orotic acid on cortical excitability processes and cerebral circulation was studied in acute experiments in cats. The effect on CNS excitability was assessed by examination of the cortical visual-evoked potentials and the recovery cycles. The flash-evoked responses were recorded from visual cortex (VC), associative cortex (AsC) and auditory cortex (AuC). The recovery cycles were determined as the ratio of the average response to the test stimulus and those to the conditioning stimulus depending on the interstimulus interval duration. For investigation of cerebral circulation the method of local cerebral rheoencephalography (REG) was used. The following REG parameters were assessed: amplitude, anacrotic sections of the curve and its relative part, and duration of the wave. The arterial blood pressure was monitored continuously. Orotic acid administration (50 mg/kg i.v.) induced a significant increase in the amplitude of the primary response from VC and AsC. Significant shortening of the peak latency of the second wave of the response in the VC was also observed. The recovery cycles examination showed a facilitation of the test response. The changes observed indicate an increase of excitability processes in the CNS. The REG changes after orotic acid indicate a cerebrovascular resistance decrease and increase in cerebral blood volume. It is assumed that increased cortical activity by orotic acid may lead to an improvement of cerebral circulation.

Proceeding from the data obtained concerning the effects of orotic acid on excitability processes in CNS and our neuropharmacological investigations, we studied its effects on cerebral bioelectrical activity in acute experiments with "encéphale isolé" and in intact animals with chronically implanted electrodes, at single and 10-day treatment periods in a setting where the spontaneous activity and that evoked by visual and sound stimulation were recorded. At a dose of 100 mg/kg i.v. orotic acid significantly increased the theta wave range and showed a tendency towards increasing the beta waves, preserving, at a somewhat lower level (in comparison with control animals), the reactions to visual and sound stimulation. Comparison with the neuropharmacological studies is good reason to conclude that orotic acid stabilizes the cortical neuronal function; it does not influence the ascendent activating reticular formation, but probably inhibits the descending polysynaptic pathways. It is suggested that besides its metabolic effect orotic acid also has an effect on brain vessels.

The effect of aligeron (5 mg/kg i.v.) and cinnarizine (10 mg/kg i.v.) on general and local depression of cortical bioelectrical activity was studied in acute experiments on cats. Asphyxic anoxia and hypoventilation hypoxia were used as models of general depression. Local depressions were caused by topical application of potassium chloride (KCl) and adenosine-5'-monophosphate (AMP) on the cortex. In hypoventilation hypoxia aligeron and cinnarizine increased cortical resistance to hypoxia and accelerated the recovery of cortical bioelectrical activity. In KCl- and AMP-induced depressions the drugs showed a protective effect manifested in a decrease of the degree and duration of the depression. In asphyxic anoxia their effect was insignificant.

The anti-hypoxic effect of prostacyclin (PGI2) was studied using the following methods: hypoventilation hypoxia and hypovolemic oligemia in cats and hypobaric hypoxia and complete ischemia by decapitation in mice. In experiments on cats PGI2 (250 ng/kg/min i.v.) led to an improvement of hypoxia-impaired EEG activity. In hypobaric hypoxia, PGI2 at all doses applied (50-500 micrograms/kg) led to a significant increase in the survival time (from 67.5% to 196%). In complete ischemia by decapitation, PGI2 at doses from 50 to 500 micrograms/kg significantly prolonged the gasping movements (from 7.8% to 20.6%). Different mechanisms of the anti-hypoxic effect of PGI2 are discussed. The effect observed would be potentially beneficial in hypoxic and ischemic states.

The anti-hypoxic effect of indomethacin (1-10 mg/kg) was studied using the following experimental methods: asphyxic anoxia in cats, hypobaric and anoxic hypoxia in mice, incomplete ischemia by bilateral carotid occlusion and hemic hypoxia in rats. In hypobaric and anoxic hypoxia the interaction of indomethacin with the effect of prostacyclin (PCl2) was investigated. Indomethacin showed an anti-hypoxic effect in all the methods used: it enhanced anoxia resistance index in asphyxic anoxia and significantly increased survival of rats and mice subjected to experimental hypoxia. Indomethacin potentiated the effect of PGl2, shifting the anti-hypoxic dose-response curve of PGl2 to the left. The possible mechanism of action of indomethacin in relation to cyclo-oxygenase inhibition is discussed.

The effect of nicergoline on cerebral blood flow (CBF), cerebrovascular resistance, the constriction of cerebral vessels caused reflectorily or by 5-hydroxytryptamine (5-HT) and on the transport of 5-HT in rat brain synaptosomes was studied using different experimental models. Nicergoline reduced cerebrovascular resistance in the carotid and vertebrobasilar system. The drug decreased carotid blood flow and local cortical CBF, preceded in some experiments by short-lasting CBF increase. Nicergoline almost completely inhibited brain vessels responses in the carotid and vertebrobasilar systems after tibial nerve stimulation. Simultaneously, inhibition of reflectory discharges of the sympathetic nerves was observed. Nicergoline showed an antiserotonin action by antagonizing the 5-HT effect on the cerebral circulation and inhibiting 5-HT-induced constriction of isolated rabbit basilar artery. The inhibition of uptake and enhancement of the release of 5-HT from brain synaptosomes indicates its ability to affect neuronal transmission in serotoninergic neurons. The effects of nicergoline are probably involved in the realization of its antimigraine action.

By means of the methods of local cerebral rheoencephalography (REG) and electroencephalography (EEG) the effect of piracetam (1-acetamide-2-pyrrolidone, Pyramem) on cerebral circulation and brain bioelectrical activity was studied in acute experiments on dogs. The following REG parameters were assayed: anacrotic section of the curve and its relative part, amplitude and dicrotic index. The influence of the preparation on the spontaneous EEG was studied by means of surface electrodes, pH, pO2, and pCO2 were determined in blood samples from femoral artery and superior sagittal sinus and arterio-venous differences of O2 (AVD-O2) and CO2 (AVD-CO2) were calculated. The arterial pressure and ECG were followed continuously. The results showed that after piracetam administration (100 mg/kg i.v.) an improvement of the REG parameters is observed: increase of the amplitude and decrease of the values of the relative part and dicrotic index. The changes observed indicated cerebro-vascular resistance decrease and increase of the cerebral blood volume. The AVD-O2 increased and the negative AVD-CO2 decreased. The EEG data indicated an improvement in the functional state of the brain cortex. Suggestions as to mechanism of piracetam effect and the usefulness of the methods were made.