Effect of mexidol on combined vascular pathology of brain and heart

The effect of mexidol on cerebral blood flow under conditions of experimental myocardial infarction and combined disturbances of cerebral and coronary perfusion in comparison with intact and false-operated rats and rats after global transient ischemia of brain was studied. It is established that mexidol (200 mg/kg) more prominently enhances the blood flow in the parietal region of brain cortex of rats with combined ischemia of brain and heart as compared to intact rats and rats after experimental myocardial infarction. Under conditions of combined pathology, mexidol produces the same cerebrovascular effect as that in animals with cerebral ischemia.     

Proceedings: Psychotropic drugs and quality of sleep: quantitative neurophysiological and subjective parameters (author's transl)]

The effect of drugs of the 3 main psychopharmaceutical classes (anxiolytics, neuroleptics, antidepressants) on objective and subjective sleep parameters was studied in healthy normal volunteers. Objective parameters included: computerclassified sleep stages, visually evaluated REM-activity as well as 22 variables of the quantitatively analyzed all-night sleep and REM-sleep EEG. Alterations of the subjective sleep quality were rated based on a sleep self-rating scale. It was found that anxiolytics, neuroleptics and antidepressants induce characteristic changes in the objective sleep parameters. Subjectively, the quality of sleep was best after anxiolytics, while the quality of awakening in the morning was dependent on the dose of the anxiolytic drug. Finally, the relationship between objective and subjective sleep parameters was explored.     

Investigation of the effects of mexidol in escapable and inescapable emotional stress in inbred BALB/C and C57BL/6 mice

The effect of mexidol administered in a dose of 100 mg/kg (i.p.) was studied in BALB/C and C57BL/6 mice on various emotional stress models including open field test, elevated plus-maze test, and passive avoidance conditioned reflex. Upon a single administration, the drug produces a selective anxiolytic action on BALB/C mice (experimental animals with a "passive" phenotype of the emotional stress reaction), while not inducing any sedative (tranquilizer) effect in C57BL/6 mice (belonging to the phenotype with "active" emotional stress reaction).     

Interaction of GABA and serotonin in the anxiolytic action of diazepam and serotonergic anxiolytics.

The general purpose of the present study was to analyze the possible interactions between the GABA-benzodiazepine and the serotonergic (5-HT) systems in the anxiolytic action of diazepam and the 5-HT1A agonists, ipsapirone, indorenate, and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The effect of the benzodiazepine receptor antagonist, flumazenil (10.0 mg/kg), on the anxiolytic action of ipsapirone (5.0 mg/kg), indorenate (5.0 mg/kg), and 8-OH-DPAT (0.125 mg/kg) was examined on the avoidance exploratory behavior paradigm in mice. The effect of the 5-HT1 blockers, methiotepin (0.31 mg/kg), pindolol (3.1 mg/kg), and alprenolol (5.0 mg/kg), on the anxiolytic action of diazepam (0.5 mg/kg) was also studied. In the last part of this work, the putative potentiation between diazepam (0.25 mg/kg) and each of the serotonergic anxiolytics was investigated. The antianxiety effect of diazepam, ipsapirone, indorenate, and 8-OH-DPAT was prevented by flumazenil. The serotonergic/beta-blocker, alprenolol, partially antagonized the diazepam effect. Finally, a potentiation of suboptimal doses of diazepam and ipsapirone, but not with indorenate or 8-OH-DPAT, was observed. The findings suggest an interaction between both systems on the anxiolytic action of diazepam and the 5-HT1A agonists.     

The actions of diazepam and serotonergic anxiolytics vary according to the gender and the estrous cycle phase

The anxiolytic effect of diazepam (0.5, 1.0 and 2.0 mg/kg), buspirone (2.5 and 5.0 mg/kg), indorenate (2.5 and 5.0 mg/kg) and ipsapirone (5.0 and 10.0 mg/kg) was evaluated in male and female rats during the proestrus and metestrus phases. The burying behavior test was used to measure the anxiety levels. In this test, increases in the behavior latency are interpreted as prolonged reactivity, while reductions in the burying behavior are considered to reflect anxiolytic states. Diazepam increases in burying behavior latency were consistently higher than those observed after serotonergic anxiolytics. Buspirone, at no dose tested, affected the burying behavior latency, while indorenate and ipsapirone had only minor effects. Male individuals were more sensitive than females to the actions of diazepam on burying behavior. The serotonergic anxiolytics produce similar responses in both sexes. Metestrus females were much less sensitive to the action of all anxiolytics on burying behavior latency than proestrus females. Proestrus females were highly sensitive to the actions of diazepam on burying latency as compared both with males and metestrus females. Data show that a larger gender and within females variation occurs after treatment with diazepam as compared with the serotonergic anxiolytics. The results are discussed considering the relationships between ovarian hormones and the GABA-benzodiazepinic and serotonergic systems.     

Effect of hydroxymethylethylpyridine succinate on the cardiac electrophysiological and hemodynamic parameters during experimental thoracotomy and acute myocardial ischemia

Effects of the natural antioxidant hydroxymethylethylpyridine succinate (mexidol) on the electrophysiological and hemodynamic cardiac parameters were studied on narcotized mongrel cats with experimental thoracotomy and acute myocardial ischemia, as manifested by sinoatrial node automatism, conduction, effective refractory period, and excitability of myocardium. The rate of contractility (dp/dtmax) in the left ventricle and the arterial pressure level (p) were monitored using a special differentiating device. The antiarrhythmic activity of mexidol was studied by ECG. The cardioprotective effect of the drug is manifested by normalization of the electrophysiological parameters during operation (accompanied by artificial lung ventilation, thoraco- and pericardiotomy). The positive effect was also observed in operated animals with acute ischemia model. The prophylactic administration of mexidol in a dose of 7 mg/kg prevented the cardio-depressant consequences of acute ischemia and reduced the risk of ventricular arrhythmia during coronary artery occlusion.     

Effects of long-term administration of anxiolytics on reticular-elicited hippocampal rhythmical slow activity.

Buspirone is effective in treating clinical anxiety but, unlike classical anxiolytics, does not have anti-convulsant, sedative or muscle relaxant side-effects and does not interact with GABA. Buspirone may also differ from classical anxiolytics in requiring a period of 2 weeks or more to achieve its full therapeutic action. It has previously been shown that all anxiolytic drugs, including buspirone, reduce the frequency of reticular-elicited hippocampal rhythmical slow activity (RSA). The present experiments tested whether the time course of the effect of buspirone on rhythmical slow activity differed from that of the anxiolytic benzodiazepine chlordiazepoxide. Rats, implanted with reticular stimulation electrodes and subicular recording electrodes, received three intraperitoneal injections per day of buspirone (2.5 mg/kg), chlordizepoxide (5 mg/kg) or saline for 45 days. Both buspirone and chlordiazepoxide reduced the frequency of rhythmical slow activity on the first day of testing and Ro15-1788 (10 mg/kg) blocked the effects of chlordiazepoxide but not buspirone. There was no increase in the effect of buspirone with time. These results showed that, if the effect of anxiolytic drugs on rhythmical slow activity provides any basis for their clinical action, then some additional factors are required to explain both the delayed action of buspirone and the immediate action of classical anxiolytic drugs.     

Housing conditions and the anxiolytic efficacy of buspirone: the relationship between main and side effects

Serotonergic anxiolytics yield contradictory results both in the laboratory and clinically. In an attempt to investigate the cause of discrepancies, the anxiolytic effect of buspirone (0, 3 or 10 mg/kg, single treatment) was tested 1 h and 4 h after injection in rats in different housing conditions. At 1 h after drug administration, buspirone increased corticosterone production and decreased locomotor behaviour in both the elevated plus-maze and the social interaction tests. No anxiolytic-like effect was produced in either test. At 4 h after drug injection, no corticosterone or locomotor effects of buspirone were observed. In contrast, anxiolytic effects emerged in this phase. Open arm exploration and social investigation were increased in the plus-maze and social interaction test, respectively. In the plus-maze, the anxiolytic effect was significant in isolated animals only. In the social interaction test, the anxiolytic effect was stronger in isolated than in group-housed animals. When corticosterone secretion was inhibited by adrenalectomy, a full anxiolytic effect of buspirone was observed 1 h after drug administration. It appears that the side effects of buspirone have a shorter duration than the main anxiolytic effect. The buspirone-induced increase in corticosterone may have abolished the anxiolytic effects of the drug shortly after injection. Individual housing enhanced the anxiolytic efficacy of buspirone 4 h after administration.     

Anxiolytic profile of GR 38032F in the potentiated startle paradigm

The potentiated startle paradigm has been demonstrated to be a model of anxiety sensitive to a range of established and putative anxiolytics. This study reports a preliminary investigation of the effects of the 5-HT(3) antagonist GR 38032F on potentiated startle. Doses of 0.01 and 0.1mg/kg each showed an anxiolytic profile in significantly reducing startle amplitude, with the lower dose having an effect comparable to chlordiazepoxide at 5.0mg/kg. 5-hydroxytryptophan at 25mg/kg significantly enhanced startle amplitude, and a mutual antagonism was found when 5-HTP was combined with GR 38032F. The results extend previous work with other models of anxiety suggesting anxiolytic potential for GR 38032F, and further demonstrate the possibility that the anxiolytic effect is mediated by serotonergic mechanisms.     

Species differences in the mechanism through which the serotonergic agonists indorenate and ipsapirone produce their anxiolytic action

The effect of three anxiolytic drugs, indorenate, ipsapirone and diazepam, on the burying behaviour of rats and mice was studied. All three drugs induced a reduction in burying behaviour interpreted as a reduction in anxiety. However, a species difference in the diazepam sensitivity was found: rats showed a clear effect after 1.0 mg/kg while already at 0.25 mg/kg an action was observed in mice. The serotonergic anxiolytics produced similar responses at similar doses (2.5–5.0 mg/kg) in both species. The serotonergic antagonists, pindolol (3.1 mg/kg), alprenolol (5.0 mg/kg) and methiotepin (0.31 mg/kg), induced a slight reduction in the time spent burying but effectively counteracted the anxiolytic action of the serotonergic agonists in mice but not in rats. By contrast, in rats, the beta blocker, practolol (0.5 mg/kg), was the only drug effective in preventing the anxiolytic actions of ipsapirone. The combined treatment of indorenate and methiotepin resulted in an impairment of motor coordination and ambulatory behaviour in both species studied, thereby suggesting that the lack of effect of such combination was mediated by altering the motor behaviour. Finally, the reduction in ambulatory behaviour in mice produced by ipsapirone was effectively prevented by the antagonists methiotepin, pindolol and alprenolol indicating the involvement of a serotonergic receptor in this effect. From these results it is concluded that a different mechanism underlies the anxiolytic actions of indorenate and ipsapirone in mice and rats.     

Behavioral effects of several new anxiolytics and putative anxiolytics

The behavioral effects of several new anxiolytics and putative anxiolytics were evaluated in two tests sensitive for anxiolytic activity. In the first test, rats were trained to lever-respond for sweetened milk under a multiple variable-interval fixed-ratio (VI-FR) schedule of reinforcement. In the FR component a brief electric shock coincided with the presentation of reward (i.e. conflict procedure). Treatment of these rats with diazepam, tracazolate, CGS-9896, and the pyrimidinylpiperazine derivatives buspirone, gepirone and ipsapirone (TVX Q 7821) significantly increased responding that was suppressed by foot-shock. A common metabolite of the pyrimidinylpiperazines, l-PP, had no affect on punished responding. A second group of rats was trained to discriminate diazepam from saline using a two-lever operant choice procedure. Diazepam-stimulus generalization occurred to CGS-9896, CL 218,872, zopiclone and tracazolate, but not to buspirone, gepirone, ipsapirone or l-PP. It was concluded that while all of the new compounds examined appear to share an anxiolytic effect as demonstrated by their activity in the conflict procedure, the pyrimidinylpiperazine agents do not share discriminative stimulus properties which are common to drugs which act via the benzodiazepine receptor.     

Comparative characteristics of antioxidant properties of hypoglycemic agents diabenol and gliclazide

The antioxidant properties of diabenol and gliclazide with reference to mexidol have been studied in vitro on several model systems, including chemiluminescence (CL) of lipids, CL with generation of reactive oxygen species (ROS), CL dependent on luminol oxidation by peroxy radicals, and the Glavind DPPH free-radical method. Diabenol exhibited the properties of a scavenger of superoxide anions and hydroxy and peroxy radicals in model CL systems with ROS generation. The activity of diabenol in inactivating ROS was about 8 times higher compared to mexidol. However, the antioxidant activity of diabenol in CL with peroxy radical generation was 3 times lower compared to mexidol. Gliclazide demonstrated dose-dependent antioxidant activity only on the model with stable DPPH radicals, where its inhibitory effect was 15 times greater than that of the reference drug.     

The effect of semax and mexidol on the course of acute pancreatitis in rats

The effect of semax and mexidol on the course of acute pancreatitis in rats was studied in comparison with the action of contrical, fluorouracil, and dibunol. It was established that a single intraductal or intraperitoneal administration of semax or mexidol markedly reduces the loss of experimental animals (to 10-13%), decreases hyperfermentemia, lipid peroxidation activation, and vascular permeability, improves microcirculation, and accelerates healing of the damaged pancreatic zones by substitutional repair of pancreatic acini not accompanied by coarse fibrous changes in the parenchyma. Upon the intraductal administration, semax and mexidol were more effective than contrical, fluorouracil, and dibunol.     

Similar effects of buspirone and chlordiazepoxide on a fixed interval schedule with long-term, low-dose administration

Buspirone is a novel anxiolytic which does not share the muscle relaxant, anticonvulsant and sedative properties of classical anxiolytics such as the benzodiazepines. Its effects on behavioural tests of anxiolytic action generally match those of classical anxiolytics provided a low dose is used. However, in a previous experiment, buspirone appeared to affect fixed interval responding in a way which differed qualitatively as well as quantitatively from the classical anxiolytic chlordiazepoxide. It takes as much as 2 weeks for the clinical effects of anxiolytics to develop, during which time the side effects of benzodiazepines undergo tolerance. We, therefore, decided to compare long-term pre-administration (60 days, three injections/day) of buspirone and chlordiazepoxide on learning of a fixed interval 60-s schedule. The doses were based on previous acute dose-response tests of hippocampal theta rhythm in freely moving animals. Buspirone (0.1 mg/ kg i.p.) and chlordiazepoxide (0.4 mg/kg i.p.) produced similar increases in responding, especially in the middle of acquisition of the fixed interval schedule. Consistent with our acute electrophysiological tests, the effects of 0.4 mg/kg chlordiazepoxide were somewhat larger than those of 0.1 mg/kg buspirone. These results suggest that the acute effects of buspirone, but probably not chlordiazepoxide, on fixed interval responding are contaminated by side effects which do not seriously affect the results with long-term administration. The effects of both novel and classical anxiolytics on control of hippocampal theta rhythm appear to predict the magnitude of their common anxiolytic effects and to be unrelated to their different side effects.     

Comparative characteristics of the psychotropic activity of "atypical" tranquilizers in an experiment

Experiments on animals were made to study pharmacological activity of "atypical" tranquilizers (nitrazepam, flunitrazepam, clobasam, tacitin, clonazepam, depakin) according to the classical methods for determination of pharmacological activity of typical anxiolytics. As regards the spectrum of pharmacological activity, "atypical" tranquilizers differ from classical anxiolytics. The anxiolytic effect exhibited by the latter group drugs with the exception of clonazepam develops in the presence of the sedative manifestations. The data obtained attest to the necessity of a comprehensive methodological approach to the assessment of "atypical" tranquilizers.     

Antihypoxic effect of 3-hydroxypyridine and succinic acid derivatives and their nootropic action in alloxan diabetes

Relationship between the antihypoxic effect of 3-hydroxypyridine and succinic acid derivatives (emoxipine, reamberin and mexidol) and their effect on conditional learning, glycemia, and lipidemia was studied in rats with alloxan-induced diabetes. In parallel, the analogous relationship was investigated for alpha-lipoic acid that is regarded as a "gold standard" in treatment of diabetic neuropathy. It was established that single administration of emoxipine and mexidol in mice in doses equivalent to therapeutic-range doses in humans produces antihypoxic effect manifested by increased resistance to acute hypoxic hypoxia in test animals. Alpha-lipoic acid is inferior to emoxipin and mexidol in the degree of antihypoxic action. Reamberin does not exhibit this effect. The introduction of emoxipin, reamberin, mexidol, and alpha-lipoic acid in rats with alloxan diabetes during 7 or 14 days in doses equivalent to therapeutic-range doses in humans corrects conditional learning disorders in direct relationship with the antihypoxic activity of these drugs. The development of the nootropic effect of emoxipin, mexidol, and alpha-lipoic acid is related to a decrease in hyperglycemia and hyperlipidemia in rats with alloxan diabetes. The nootropic action of reamberin is accompanied by a transient hypoglycemizing effect and aggravation of dyslipidemic disorders. The antihypoxic activity of investigated drugs determines the direction and expression of their lipidemic effect, but is not correlated with the hypoglycemizing action these drugs on test animals with alloxan diabetes.     

Effects of long-term administration of imipramine on reticular-elicited hippocampal rhythmical slow activity

All anxiolytics so far tested show a common reduction in the frequency of reticular-elicited hippocampal rhythmical slow activity (RSA). The present experiments tested whether imipramine, an antidepressant drug which has also been used to treat generalized anxiety disorders, shares the common characteristics of anxiolytics on hippocampal RSA. Rats implanted with reticular stimulating electrodes and subicular recording electrodes received both acute and chronic injection of different doses of imipramine. Only relatively high doses (20 and 30 mg/kg, IP) of imipramine produced a reduction in RSA frequency after a single administration. Long-term administration of 20 mg/kg (but not 10 mg/kg, IP) imipramine induced anincrease in baseline RSA frequency but there was no change in the acute frequency-reducing effect of the drug. These results suggest that changes in hippocampal RSA reflect different mechanisms of action for chronic versus acute treatment with antidepressant. It is possible that, at high doses, apparently anxiolytic effects of imipramine may be mediated by similar mechanisms to conventional anxiolytic drugs.     

Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors

The role of cannabinoid CB(1) receptors in the action of anxiolytics was examined. Deletion of CB(1) receptors resulted in increased anxiety-like behaviours in light/dark box, elevated plus maze and social interaction tests. Mutant mice presented basal low corticosterone concentrations and low proopiomelanocortin gene expression in the anterior lobe of the pituitary gland compared to wild-type mice. Ten minutes of restraint stress resulted in a twofold increase in corticosterone concentrations in the plasma of mutant mice, compared to wild-type mice. Bromazepam (50 or 100 microg/kg) markedly increased the time spent in light area in wild-type animals, though both doses were without effect in mutant mice. Administration of buspirone (1 or 2 mg/kg) produced anxiolytic effects in wild-type mice. In contrast, only the highest dose of buspirone had anxiolytic results in mutant mice. Our findings reveal that CB(1) receptors are involved in the regulation of emotional responses, and play a pivotal role in the action mechanism of anxiolytics. They suggest that alterations in the functional activity of the CB(1) receptor may be related to the emergence of anxiety disorders, and may affect treatment with anxiolytics.     

Mexidol-induced modification of lipid metabolism in pancreatitis

The chronic experiments on mongrel dogs with a model pancreatitis showed that mexidol decreases manifestations of the inflammatory process. The treatment with mexidol led to a decrease in the degree of lipid transformations in the initial stage of pancreatitis development, with normaliation of the lipid metabolism according to the liver and blood plasma characteristics. The membranoprotector effect of mexidol, manifested in normalization of the lipid spectrum, is probably related to inhibition of the lipid peroxidation (LPO) process and to a decrease in the activity of phospholipase A2. The correlation between lipid metabolism, LPO, and phospholipase A2 activity in the tissues studied indicates that the therapeutic effect of mexidol in animals with pancreatitis is based on the cytoprotector activity of the drug.