Vol 15, No 3 (2024)

BACKGROUND: The body’s response to hypoxia is largely determined by individual sensitivity to it. It has been shown that subjects with high resistance to hypoxia (humans and animals) are less susceptible to the damaging effects of hypoxia on the brain, myocardium, liver, and kidneys.

AIM: The experimental study of the antioxidant effects (indicators of lipid peroxidation and the activity of antioxidant systems in the brain) of 2-ethylthiobenzimidazole and a complex of succinic acid salts (amosuccinate) and their combination to increase individual brain resistance to hypoxia during interval hypoxic hypobaric training in rats.

MATERIALS AND METHODS: Acute hypoxic hypobaric hypoxia was induced in a flow pressure chamber. Rats were divided according to their resistance to acute hypoxia, raising them in a pressure chamber to a height of 11,000 m at a speed of 50 m/s and exposing them at altitude until agonal breathing occurred. Rats that were exposed to hypoxia for 5–10 minutes were considered low-resistant, and those exposed to hypoxia for more than 10 minutes were considered highly resistant. The interval hypoxic training regimen was 3 days. A one-day training cycle consisted of raising rats 6 times at a speed of 15 m/s to an altitude of 5000 m and exposing them to the height for 30 min. The interval between lifts is 20 minutes. The work used the synthetic adaptogen 2-ethylthiobenzimidazole hydrobromide (metaprot) 25 mg/kg and a complex of succinic acid salts (amosuccinate) 50 mg/kg, which were administered intraperitoneally for 3 days immediately after the end of a one-day training cycle. The control group consisted of trained and untrained rats that received saline. In the brain, the content of lipid peroxidation products (diene conjugates, malonic dialdehyde) was determined and the state of antioxidant systems was assessed (the content of reduced glutathione, the activity of catalase and superoxide dismutase).

RESULTS: Acute hypoxia caused excessive lipid peroxidation and decreased activity of antioxidant systems. Metaprot and amosuccinate in combination with hypoxic training prevented lipid peroxidation in the brain of rats. The content of diene conjugates in the brain of rats decreased by 12–26%, malonic dialdehyde by 13–58%. The drugs increased the content of reduced glutathione by 42–76%, catalase by 1.5 times, and superoxide dismutase by 1.5–2.2 times. The effect of the combined use of metaprot with amosuccinate was greater than that of the drugs alone.

CONCLUSIONS: The combination of high-altitude training with the use of synthetic alaptogens (metaprote and amosuccinate) increases the adaptive capabilities of the brain, which is confirmed by both an increase in survival time at altitude and a decrease in excessive lipid peroxidation and restoration of antioxidant systems.

BACKGROUND: Intense and prolonged stress can be detrimental to both psychological and physical health. Stress often leads to the development or worsening of compulsive overeating. Compulsive overeating is characterized by recurrent episodes of consuming large amounts of food, accompanied by a sense of loss of control.

AIM: To study the effects of the ghrelin receptor antagonist Agrelax on compulsive overeating induced by acute and chronic stress in rats.

MATERIALS AND METHODS: The study involved 150 male and 15 female Wistar rats. To simulate compulsive overeating, the animals received a high-calorie mixture based on chocolate paste three times a week, while maintaining free access to standard food and water. Compulsive behavior was assessed using the marble burying test. Different groups of animals were exposed to various stressors, including maternal deprivation, limb electrical stimulation, partial sensory and complete social isolation, and acute vital stress. Agrelax, a ghrelin receptor antagonist, was administered intranasally at a dose of 1 μg/μL, 10 μL in each nostril, for 7 days.

RESULTS: Compulsive behavior was evaluated using the marble burying test. The experimental group on a high-calorie diet buried significantly more marbles than the control group (p < 0.01). After a 7-day course of Agrelax, the number of buried marbles significantly decreased, reaching the control group values (p < 0.05). A model of compulsive overeating in rats was successfully developed by providing high-calorie food three times a week. After a 7-day course of Agrelax, the consumption of high-calorie food significantly decreased (p < 0.05). Limb electrical stimulation significantly increased the consumption of high-calorie food (p < 0.05). After a 7-day course of Agrelax, the consumption of high-calorie food significantly decreased (p < 0.01). Maternal deprivation stress significantly increased the consumption of high-calorie food (p < 0.001). After a 7-day course of Agrelax, the consumption of high-calorie food decreased, reaching the control group values. In animals raised under partial sensory and complete social isolation, Agrelax did not significantly reduce the consumption of high-calorie food. In animals subjected to acute vital stress, Agrelax did not reduce the consumption of high-calorie food.

CONCLUSIONS: The data obtained suggest new ways for synthesizing peptide pharmacological agents based on ghrelin and its antagonists to treat eating disorders.

Alzheimer’s disease is caused by the loss of synaptic connections and neurons in the brain. One of the characteristic morphological features of Alzheimer’s disease is the formation of amyloid plaques containing β-amyloid peptide. The β-amyloid peptide is produced from the amyloid precursor protein (APP) through sequential proteolytic cleavages by α-secretase, β-secretase, and γ-secretase, resulting in β-amyloid peptide clustering into amyloid plaques, a key pathogenic event in Alzheimer’s disease. Since γ-secretase mediates the final cleavage that releases β-amyloid peptide, it has been widely studied as a potential drug target for the treatment of Alzheimer’s disease. γ-Secretase is a transmembrane protein complex consisting of four subunits: presenilin, nicastrin, Aph-1, and Pen-2, which are necessary for its function. γ-Secretase has been shown to cleave more than 140 substrates, including the APP and Notch. Clinical trials of γ-secretase inhibitors for Alzheimer’s disease have shown side effects due to inhibition of Notch signaling. It has been concluded that alternative compounds with more specific regulation or modulation of γ-secretase are needed. A number of γ-secretase modulators have now been developed. To modulate γ-secretase and better understand its complex biology, research focuses on identifying inhibitor and modulator binding sites within γ-secretase’s structure, as well as intermediate binding proteins that modulate γ-secretase. This article discusses recent advances over the past decade in studying the role of γ-secretase in the treatment of Alzheimer’s disease.

Sergei V. Anichkov (1892–1981) is a Doctor of Medical Sciences, Professor, Academician of the USSR Academy of Medical Sciences, and laureate of the Lenin and USSR State Prizes, led the Department of Pharmacology at the Institute of Experimental Medicine from 1948 to 1981. Initially, the department comprised three laboratories with a limited staff. To advance research, Anichkov, who headed the Department of Pharmacology at the Sanitary and Hygienic Medical Institute, brought together the resources of this Department and the Department of Pharmacology of the Institute of Experimental Medicine, further expanding them, primarily through the addition of postgraduate students such as S.S. Krylov, P.P. Denisenko, V.G. Startsev, V.E. Ryzhenkov, Yu.S. Borodkin, I.S. Zavodskaya, and others. Anichkov established a scientific school of pharmacologists, and many significant achievements of the Department of Pharmacology at the Institute of Experimental Medicine are associated with his name. Young postgraduate students, passionate about research work, became the first or senior disciples and followers of the scientific school of pharmacology of academician Anichkov. Clinical and experimental studies conducted on the use of neurotropic agents for the treatment of gastroduodenal and cardiovascular disorders made it possible to propose a fundamentally new approach to treating peptic ulcer disease, ischemic heart disease, myocardial infarction, and tonsillogenic cardiopathies, depending on specific conditions and stages of the disease. It was substantiated that the administration of neuroblockers to patients is advisable only in the acute phase of the disease, when there is an excessive flow of nerve impulses that cause and maintain the pathological process. However, when acute symptoms cease and the reparative phase begins, the suppression of nerve impulses may slow down the reparative processes. At this stage, as indicated by experimental and clinical data, the use of agents that normalize the trophic function of the sympathoadrenal system and stimulate tissue energy metabolism is recommended. In 1946, Anichkov proposed to divide the cholinoreactive systems into muscarine-sensitive and nicotine-sensitive types. From that time, the pharmacology of central anticholinergics became an important issue for the Anichkov›s school for many years. A number of neurotropic drugs from various classes were proposed for the pharmacological treatment of hormonal disorders. One of them was the original drug Etimizol (Ethimizole), which activates the hypothalamus-pituitary-adrenal cortex system and increases the sensitivity of the adrenal cortex to the action of adrenocorticotropic hormone, which allowed the drug to be recommended for asthma and various inflammatory diseases.