The experimental study of the antihypoxic properties of harmine hydrochloride

A derivative of the beta-carboline alkaloid harmine — the drug harmine hydrochloride was studied for the presence of antihypoxic properties in models of hypobaric hypoxia and normobaric hypoxia with hypercapnia. It was found that harmine hydrochloride does not have a signifi cant compensatory effect in the normobaric hypoxia test with hypercapnia. At the same time, harmine hydrochloride in small doses (2.5 and 5 mg/kg) has antihypoxic activity in the hypobaric hypoxia test, which is expressed in a statistically signifi cant increase in the life expectancy of animals treated with the drug, compared with the control, in conditions of hypoxia. According to the antihypoxic effect, harmine hydrochloride at doses of 2.5 and 5 mg/kg was found to be comparable with the reference drug (mexidol, 100 mg/kg).

Evaluation of the activity of antihypoxants with an isothiourea structure in a model of hypercapnic hypoxia with a shutdown of the cerebral hemispheres

PURPOSE: To study the effect of amtizol, 2-aminobenzthiazole (2-ABT) and 2-amino-4-acetylthiazolo[5,4-b]indole (BM-606) on the resistance of male outbred mice to acute hypoxia with hypercapnia under conditions of isolated functioning of one from the hemispheres, as well as both hemispheres of the brain. METHODS: A model of acute hypoxia with hypercapnia (canned hypoxia) was used in mice of the same mass, the lifespan of all animals was determined. Temporary shutdown of the cortex of one of the hemispheres or both hemispheres was achieved by epidural application of filter paper moistened with 25% potassium chloride solution, creating a spreading depression according to Leao. Amtizol, 2-aminobenzthiazole (2-ABT) and 2-amino-4-acetylthiazolo[5,4-b]indole (BM-606) at equimolar doses of 25, 32.5, and 50 mg/kg, respectively were used as pharmacological analyzers, the compounds were injected intraperitoneally 30 min before the hypoxic episode. RESULTS: It was shown that, in contrast to amtizol, 2-ABT and VM-606 increase the life time of experimental animals when any hemisphere is turned off. The use of drugs when both hemispheres were turned off revealed that amtizol has approximately equal effect on the brain and the rest of the body, in 2-ABT antihypoxic activity is 1/3 associated with the brain, in VM-606 exclusively with the brain. CONCLUSION: The experimental model used in this work makes it possible to quite easily evaluate the effect of either one drug or compare several drugs, their role in the functioning of the cerebral hemispheres, on which part of the sample highly resistant or low resistant to hypoxia they have the greatest effect.

INFLUENCE OF DEUTERIUM-DEPLETED DRINKING DIET ON THE FUNCTIONAL STATE OF THE CENTRAL NERVOUS SYSTEM OF ANIMALS UNDER RATE AND NORMOBARIC HYPOXIA WITH HYPERCAPNIA

The effect of long-term (42 days) introduction of deuterium-depleted water into the diet of rats on the functional state of the central nervous system under normal conditions and normobaric hypoxia with hypercapnia was studied. It was also established that the use of deuterium-de-pleted water both under normal conditions and after stressful exposure contributes to a sig-nificant decrease in the emotional anxiety of animals. Long-term use of deuterium-depleted water before hypoxic exposure (exposure to the amnestic factor) contributes to the preservation of learning and memory at the control level, i.e. has a pronounced protective antiamnesic effect.

The influence of new coumarin derivatives on survival rate of mice in model conditions of acute hypoxia

Objective. The article is devoted to study the anti-hypoxemic properties of new coumarin derivatives in the models of hypoxemic hypoxia with hypercapnia, hemic hypoxia and histotoxic hypoxia. Materials and methods. Нypoxemic hypoxia with hypercapnia was modeled as follows: mice were placed in hermetic 200 cm3 jars one in a jar. Hemic hypoxia was reproduced in mice by single subcutaneous introduction of sodium nitrite in a dose of 230 mg/kg. Histotoxic hypoxia was caused in mice by intraperitoneal introduction of sodium nitroprusside in a dose of 20 mg/kg. Coumarin derivatives under lab codes IEM-2266 and IEM-2267 were dissolved in distilled water with addition of twin-80, and then a single intraperitoneal infusion of them in doses 25 and 50 mg/kg was made 45 minutes before placing to the model conditions. Increased life time of an animal compared with the control served the criterion of anti-hypoxemic effect of the studied substances. Results. In hypoxemic hypoxia with hypercapnia test compound under IEM-2267 in doses of 25 and 50 mg/kg increased mice life time by 26 and 34% respectively in comparison with control. In hemic hypoxia model, the positive effect was seen with IEM-2266 compound in a dose of 50 mg/kg which increased life time of animals by 45% in comparison with control. In histotoxic hypoxia model, at preventive introduction of IEM-2266 compound in a dose of 25 mg/kg and IEM-2267 in a dose of 50 mg/kg life time increased up to 117% and 123% respectively. Conclusion. The coumarin derivatives IEM-2266 and IEM-2267 relieved the course of acute hypoxia and increased life time of animals in the models of hypoxemic hypoxia with hypercapnia, hemic hypoxia and histotoxic hypoxia.

ВЛИЯНИЕ ОБЕДНЕННОГО ДЕЙТЕРИЕМ ПИТЬЕВОГО РАЦИОНА НА ФУНКЦИОНАЛЬНОЕ СОСТОЯНИЕ ЦЕНТРАЛЬНОЙ НЕРВНОЙ СИСТЕМЫ ЖИВОТНЫХ В УСЛОВИИ ГИПОКСИИ

The effects of prolonged (42 days) addition of deuterium-depleted water into rat’s diet on the functional state of the central nervous system in normal conditions and under conditions of normobaric hypoxia with hypercapnia were studied. It was also established that the use of deuterium-depleted water both in normal conditions and after exposure to oxidative stress contributes to a significant reduction in the emotional anxiety of animals. Prolonged use of deuterium-depleted water before hypoxic exposure (amnestic effect) helps to maintain learning and memory at the control level, i.e. it has a pronounced protective antiamnestic effect. In normal conditions, deuterium-depleted water does not affect the learning ability of animals.

INVESTIGATION OF THE ANTIHYPOXIC PROPERTIES OF NEW NICOTINIC ACID DERIVATIVES

Two of the five new nicotinic acid derivatives proved to have the antihypoxic properties in tests with mice exposed to acute normobaric hypoxic hypoxia with hypercapnia. Specifically, LKhT 4–19 (100 mg/kg) extended lifetime of the animals by 11 %; LKhT 6-19 doses of 50 and 100 mg/kg extended lifetime by 23 and 34 %, respectively. The antihypoxic effect of LKhT 6–19 (50 mg/kg) outperformed in 1.2 times mexidol (substance of comparison) at the similar dose and was highly competitive at the dose of 100 mg/kg. For reference, mexidol is a 3-hydroxypyridine derivative (ethylmethylhydroxypyridine succinate incorporating, similar to the substances in question, the pyrydine heterocycle). Besides, LKhT 6–19 (100 mg/kg) outperformed mexidol at the similar dose in 1.1 times.

MECHANISMS OF ANALEPTIC AND ANTIGYPOXIC EFFECTS OF HETEROSIDES - DERIVATIVES OF SULFUR AND NITROGEN-CONTAINING HETEROCYCLES

In order to expand the theoretical basis of the purposeful search of analeptics, the awakening and antihypoxic properties of heteroside-21, heteroside-31 (derivatives of sulfur- and nitrogen-containing heterocycles) were studied and the mechanisms of their action were established. Sodium thiopental (42 mg/kg) was used to simulate suppression of the respiratory and vascular centers of the brain. The comparison drugs were – sulfocamphocaine (SCC) with combined analeptic action (20 mg/kg) and the antihypoxic drug piracetam (300 mg/kg). The results were obtained on the models of thiopental anesthesia and normobaric hypoxia with hypercapnia. The analysis of data allowed to count qualitatively and quantitatively the arousing and antihypoxic activity of new substances and classical drugs; their effect on the respiratory center of the brain and behavioral responses of animals; theoretically substantiate, experimentally confirm and establish aerobic, anaerobic and detoxification mechanisms of realization of effects in various conditions; to formulate the theoretical bases of purposeful search of universal analeptics and antihypoxic drugs and offer an instrumental-methodological complex for their experimental reproduction.