Neuroprotective and Antiamnestic Effects of a New Drug Emopag in Rats.

Emopag, a new drug, preventively administered in doses of 10 and 30 mg/kg/day over 4 days produced a pronounced neuroprotective effect in the model of brain ischemia caused by gravitational overload and reduced animal mortality from 17 to 0%. The preparation more effectively corrected neurological deficit than the reference drugs Mexidol (in considerably larger doses of 30 and 90 mg/kg/day) and antihypoxic drug amtizol (30 mg/kg/day). Moreover, Emopag exhibited considerable antiamnestic activity comparable to that of Mexidol (in 3-fold higher doses); in a dose of 30 mg/kg/day Emopag was more effective than Mexidol and amtizol in the same dose. Thus, Emopag showed marked neuroprotective and antiamnestic effects in the model of gravitational overload in rats.

[STUDYING SOME PHARMACOLOGICAL EFFECTS OF NEW 3-HYDROXYPYRIDINE DERIVATIVE].

It was established that a new 3-hydroxypyridine (3-HP) derivative, 2-ethyl-6-methyl-3-hydroxypyridine L-aspartate (3-HP), in small doses (1 and 5 mg/kg) increased physical performance in treadmill and swimming tests on rats. The new substance showed greater or equal effects compared to the reference actoprotector drugs metaprot and ladasten in much higher doses. The gluconeogenesis inhibitor tryptophan significantly (74 ± 5%, p < 0.01) prevented this stimulatory effect of 3-HPA in the treadmill test on rats. 3-HPA at a higher dose (30 mg/kg) had marked antiamnesic effect on various models of amnesia in mice. It was more effective than reference drugs mexidol (another 3-HP derivative) in a dose of 30 mg/kg and nootropic drug piracetam in a dose of 200 mg/kg, but had equal effect with these drugs in doses of 50 and 800 mg/kg, respectively. 3-HPA (30 mg/kg per day) had neuroprotective effect in rats with brain ischemia and decreased the neurologic deficiency more effectively than mexidol (50 mg/kg per day).

ACTION OF NEW 3-HYDROXYPYRIDINE DERIVATIVES WITH ANTI-NAUPATHIA PROPERTIES ON CENTRAL NEURONS.

Experiments with cats showed that microinjections into the lung of new 3-hydroxypyridine derivatives SK-119 and IBKhF-27 had a direct action on 50 and 84 % of medial vestibular nucleus (MVN) neurons respectively. The inhibitory response to the compounds was observed 6 and 25 times more frequently than exciting; inhibition by IBKhF-27 was observed 1.9 times more frequently than by SK-119. Also, microinjections of SK-1 19 and IBKhF-27 acted directly on 44 % and 81 % of cat's Purkinje cells, respectively. In case of Purkinje cells, the inhibitory reaction was seen 5.5 and 25 times oftener than exciting, respectively, and inhibition by IBKhF-27 occurred 2.1 times more frequently than by SK-119. Investigations of rat's cerebellum sections evidenced that 5 mM of IBKhF-27 inhibited population responses of Purkinje cells 95 1 3 %. In the presence of specific noncompetitive NMDA-receptor antagonist (MK-801, 100 pM) the depressive effect was annulled almost fully by 96 * 2 %. It follows that IBKhF-27 nearly entirely inhibits synaptic transmission from cerebellar parallel fibers to Purkinje cells, while MK-801 has a similarly strong anti-depression effect that testifies the involvement of the NMDA-receptor complex predominantly.

Effect of NMDA, a Specific Agonist to NMDA Receptor Complex, on Rat Hippocampus.

Removal of Mg2+ ions from perfusion medium provoked epileptiform activity in CA1 field of surviving rat hippocampal slices manifested in generation of extra population spikes. MK-801 (100 µM), a specific non-competitive antagonist to NMDA-receptor complex, prevented this effect. NMDA (20 µM), the specific agonist to this complex, produced no significant effect on the orthodromic population spikes, but when applied at concentrations of 30 or 40 µM, it inhibited them partially (by 21-28%) or almost completely (by 98-99%), correspondingly. Thus, depending on concentration, NMDA can inhibit the synaptic transmission in Schaffer collaterals-hippocampal CA1 pyramidal neurons axis without triggering the epileptiform activity. D-AP5 (50 µM), a competitive antagonist to NMDA-receptor complex, completely prevented the inhibitory effect of NMDA (40 µM). While MK-801 (100 µM) almost completely prevented the inhibitory effect of NMDA, it did not eliminate it when applied after the agonist. Thus, MK-801 can prevent the inhibitory action of NMDA on synaptic transmission in Schaffer collaterals-hippocampal CA1 pyramidal neurons axis via blocking the channel of NMDA-receptor complex, while NMDA exerts its effect only via activation of NMDA receptors.

[A new approach to the search for vestibuloprotectors].

The results of experimental clinical testing of the antinaupathia action of as new compounds, so motion sickness medications (promethazine, ikaron-1 etc.) are presented. Russian medication mexidol, a derivative of 3-hydroxypyridine (3-HP) demonstrated the ability to control motion sickness in humans and animals; however, unlike reference vestibuloprotector scopolamine, it does not practically produce side-effects. Mexidol acts through ion pathways with the involvement of glutamate and GABA-ergic components. Revealed 9 of new 3-HP derivates with an antimotion sickness effect in rats, three exceeded in efficacy mexidol, and also reference medications (i.e. scopolamine and promethazine). Melatonin achieves a better vestiboloprotective effect in rats than promethazine and melatonin-ergic antidepressant agomelatine through the involvement of melatonin MT1-, MT2- and GABA(A)-receptors. Also, combinations of melatonin with mexidol or promethazine possess a distinct vestibuloprotective effect, as melatonin enhances the action of equally mexidol and promethazine. Analysis of our results and investigations of other authors infer that search for potent vestibuloprotectors should be extended to new 3-HP derivatives and melatoninergic compounds. Individual medications by themselves and in combinations can become a solution to the problem.

[STUDIES OF THE ANTIHYPOXIC AND ANTIAMNESTIC EFFECTS OF MELATONIN IN ANIMALS].

Experiments with mice showed that in a multitude of acute hypoxia models (normobaric hypoxic hypoxia with hypercapnia, hypobaric, hemic and histotaxic) the antihypoxic action of a single intra-abdominal dose of melatonin surpasses greatly amtisol, the standard antihypoxic agent. Single melatonin injection produced a strong antiamnestic action on various amnestic models (scopolamine-induced, acute normobaric hypoxia with hypercapnia, and a combination of extreme factors) which was much better than of pyracetame, a well-known nootropic (mind-stimulating) drug. Increase of the melatonin dose from 1 mg/kg to 20 mg/kg amplified both the antihypoxic and antiamnestic effects. Melatonin inhibited orthodromal population responses in surviving sections of rat's hippocampus (by 24 ± 3% at 2 mM; by 72 ± 6% at 5 mM). Besides, the inhibiting action of lusindol, a blocker of melatonin receptors MT1 and MT2--was virtually fully neutralized. Therefore, melatonin inhibits transmission within the Schaffer collateral--CA1 pyramidal neurons synapse by stimulation of melatonin receptors MT1 and MT2; higher melatonin concentrations (0.5 to 5 mM) enhance its effectiveness.

[VESTIBULAR AND THERMOPROTECTIVE PROPERTIES OF A NEW ACTOPROTECTOR].

In experiments with rats, a new 3-hydroxypyridine (3-HP) derivative--2-ethyl-6-methyl-3-hydroxypyridine L-asparaginate (30 mg/kg)--exhibited a strong vestibuloprotective effect which was better than of promethazine (50 mg/kg), a well-known vestibuloprotector Besides the new actoprotector was competitive with another 3-HP derivative, namely, mexidol (ethyl-methyl-hydroxypyridine succinate) (100 mg/kg). Moreover, a distinct thermoprotective effect of 2-ethyl-6-methyl-3-hydroxypyridine L-asparaginate (30 mg/kg) in mice was not worse than that of mexidol or metaprot (ethylthiobenzimidasol, former name bimethy), an actoprotector with good thermoprotective properties. To conclude, owing to the membrane-protective and antioxidative qualities, the vestibuloprotective and thermoprotective properties of 2-ethyl-6-methyl-3-hydroxypyridine L-asparaginate are better or competitive with the reference preparations.

Hormonal status and fluid electrolyte metabolism in motion sickness.

In the first experimental series, 10 healthy male test subjects with a high susceptibility to motion sickness showed a significant increase of ACTH, cortisol, STH, prolactin, ADH, aldosterone concentrations, and plasma renin activity after vestibular tests. The 10 subjects with a moderate susceptibility exhibited a still higher increase of the hormones, except plasma renin. The 8 test subjects with a low susceptibility displayed a considerable increase in ACTH, cortisol, and STH after vestibular stimulation. In the second experimental series, the increase of STH, cortisol, ADH, aldosterone and renin occurred immediately after rotation in the moderate susceptibility subjects and an hour after exposure in the high susceptibility subjects. This may be indicative of specific immediate adaptation mechanisms or excitation transfer in the CNS in high susceptibility persons. In the third experimental animal series, the permeability of the blood-brain barrier for 125I and IgG increased after rotation. Greater concentrations of potassium, chloride, and urea in CSF are suggestive of an inhibition process activation in the CNS and, probably, of an active urea transport by the vascular plexus epithelium which maintains constant osmotic pressure of cerebral extracellular fluid and prevents hyper-hydration of CNS neurons.

The effect of low frequency peripheral stimulation on the tail-flick reflex and evoked cortical potentials in the rabbit.

The effects of low frequency peripheral electrical stimulation of innocuous intensity (LES) on the tail-flick latency and the amplitude of the late component of the cortical potentials evoked by single electrical stimuli (20-40 ms latency) were studied in 59 awake and restrained rabbits. Increase of the tail-flick latency and profound decrease of the amplitude of the late positive component of evoked cortical potentials was observed in 50 animals. Five animals of this group and five animals from a group of 9, resistant to electrostimulation, were tested to the analgesic effects of morphine using the same criteria. Positive effects were found in the former but not in the latter group. Naloxone (0.1 mg/kg) profoundly decreased the effects of LES which suggests that an opioid mechanism is involved in the action of conditioning electrostimulation. Pretreatment of the animals with serotonin depletor p-CPA resulted in partial blockade of the effects of LES. The blockade was removed by administration of serotonin precursor 5-HTP. This is in agreement with the hypothesis that the opioid effects are partially exerted through serotoninergic descending pathways.