[Study of neuroprotective, antihypoxic and antiamnesic effects of new mixture of tripeptides].

A new mixture of tripeptides (NMT: H-Lys-Asp-Glu-OH, H-Asp-Glu-Pro-OH, H-Asp-Glu-Arg-OH) in doses of 150 and 300 mg/kg per day produces clearly pronounced neuroprotective effect in rats with brain ischemia and decreases neurologic deficiency 1.1 times more effectively than reference drug semax. NMT (10, 50 and 150 mg/kg) had marked antihypoxic effect on mice in hermetic and altitude chamber. NMT in doses of 10 and 50 mg/kg was more effective than semax in hermetic chamber (1.3 and 1.5 times, respectively) and in a dose of 150 mg/kg in altitude chamber (1.9 times). NMT (50 and 150 mg/kg) had also marked antiamnesic effect on model amnesia caused by scopolamine in rats and was more effective (1.5 and 1.4 times, respectively) than semax in equal doses. NMT (50 and 150 mg/kg) also had marked antiamnesic effect on model amnesia caused by maximal electroshock and complex extreme factors in mice and in both doses was 4 times more effective than semax on the first model and in a dose of 150 mg/kg was 2.9 times more effective on the second model. NMT (50 mg/kg) increased the amplitude of transcallosal evoked potential in rat brain by 69% and was more effective than semax in equal dose. Thus, NMT is a promising neurotropic drug with neuroprotective, antihypoxic and antiamnesic activity.

[Study of some pharmacological properties of a new adenine derivative].

It is established that the new compound, 9-[2-(4-isopropylphenoxy)ethyl]adenine (9-IPE-adenine) in a dose of 10 mg/kg per day produces neuroprotective effect in rats with brain ischemia model. 9-IPE-adenine decreased the neurologic deficiency 1.2 times more effectively (p < 0.05) than the reference drug mexidol in analogous dose, and had equal effect with this drug at 25 mg/kg per day on the neurologic deficiency and survival of animals. Electrophysiological studies in hippocampal slices in rats showed that 9-IPE-adenine depressed orthodromic population spikes in CA1 area by 42 ± 4%. Non-competitive antagonist of NMDA receptor complex MK-801, in contrast to D-AP5 (competitive NMDA receptor antagonist) and CNQX (competitive AMPA receptor antagonist), enhanced the depressive effect of the new drug more than two times. These ese results are indicative of the ability of 9-IPE-adenine to modulate the ion channel of NMDA receptor complex.

[The antiamnestic effect of nootropic substances in rats].

It has been established in experiments in rats that some nootropic substances (oxyracetam, aniracetam, nooglutil, mexidol, new 3-hydroxypyridine derivative SK-170, piracetam and noopept) produce marked antiamnestic effect on various models of amnesia (induced by microwave irradiation, acute hypoxia, and motion sickness). At the same time, meclophenoxate exhibited antiamnestic effect in the first and second models of amnesia, while 9-aminoacridine derivative HTOS-404 was only effective in the model of amnesia caused by microwave irradiation. The antiamnestic effect of nooglutil and SK-170 was caused to a significant degree by activation of non-NMDA receptors of excitatory amino acids (generally AMPA receptors), while the effect of mexidol was related to GABA(A) receptors.

[Comparative studies of antihypoxic, neuroprotective and analgesic action of succinate-containing drugs].

Experiments with mice showed that, unlike reamberin (100 mg/kg), mexidol (100 mg/kg) and cytoflavin (1 ml/kg) act as antihypoxants in pressure and hermetic chambers but not in case of acute hemic and histotoxic hypoxia. Amtisol succinate (100 mg/kg), a reference antihypoxant, excels the other tried succinate-containing drugs in all models of acute hypoxia except the hermetic chamber. In addition, the neuroprotective action of mexidol (100 mg/kg/d) and cytoflavin (100 ml/kg/d) in rats with induced ischemic stroke which was stronger than that of reamberin and amtisol succinate (100 mg/kg/d). Besides, mexidol (100 mg/kg) but not cytoflavin (1 ml/kg), reamberin or amtisol succinate (100 mg/kg) had a distinct analgesic effect in rabbits. On the neuronal level, mexidol interacts with the GABAA- benzodiazepine-receptor complex in nearly 60% cells and inhibits ion currents through the NMDA-receptor ion channels in nearly 80% neurons.

[Actiprotective and antihypoxic action of new heteroaromatic antioxidants].

Expernents with mice showed that most of 15 new heteroaromatic antioxidant compounds possess aciprotective and antixopixic properties. Based on results of treadmill and swimming tests, actiprotective action of IBKhF-1, 11 and 14 surpassed greatly bemythil and bromanthane in ordinary conditions. Inhibitor of gluconeogenase tryptophan cancelled largely the stimulatting action of highly effective and active IBKhF-1, 2 and 11 on physical performance during treadmill exercise. Consequently, gluconeogenesis activation is one of the major components of the actiprotective action of these antioxidants. In addition, IBKhF-1, 11 and 14 excelled bemythil and bromanthane in the extreme conditions of running in hyperthermia and swimming in acute hypoxia combined with hypercapnia. IBKhF-2 and 14 were better than amtisol (standard antihypoxic agent) and bemythil against acute hypoxia in pressure chamber, whereas IBKhF-4 and 14 excelled these agents in thermal chamber.

[Antihypoxic and antiamnesic effects of mexidol and semax].

Upon single administration, mexidol and semax only in doses of 100 and 0.05 mg/kg, respectively, produced an antihypoxic effect on mice in the altitude chamber and hermetic chamber tests. Preventive course administration of mexidol and semax for 6 days gave significant antihypoxic effect on the model of acute hypobaric hypoxia in mice in doses of 75 and 0.1 mg/kg per day, respectively, in which the same preparations upon single administration were ineffective. Neither mexidol nor semax upon single administration were effective on the models of acute hemic and histotoxic hypoxia. On various models of amnesia (except that induced by the maximal electroshock) in mice, both mexidol and semax exhibited marked antiamnesic effects comparable with that of the reference nootrope drugs piracetam and oxyracetam. Mexidol showed a linear, while semax exhibited a bell-shaped reversible dose-effect relationships. Mexidol and semax inhibited the ortho- and antidromic population response spikes of CA1 pyramidal neurons of survival hippocampal slices in rats. It was estimated that mexidol (in contrast to semax) increased oxygen consumption in rat brain mitochondria and had a linear dose-effect relationship in a concentration range of 1-5 mM. It is concluded that mexidol should be used in high doses (for both single and course administration) for obtaining antihypoxic and antiamnesic effects, while semax requires a thoroughly controlled choice of dosage.