Role of free radical oxidation, hypoxia and their correction in COVID-19 pathogenesis

Author:
A.V. SCHULKIN, A.A. FILIMONOVA

Academician I.P. Pavlov Ryazan State Medical University of the Ministry of Healthcare of Russia

Summary:
In following review, the pathogenesis of coronavirus disease of 2019 (COVID-19), the features of the SARS-CoV-2 virus, are shown in peculiarities. Due to big importance of oxidative stress and hypoxia in the development of this infection paid to, it has been suggested that the use of antioxidants and antihypoxants in the complex treatment of COVID-19 may be useful and significantly improve the course of the disease.
Key words: COVID-19, coronaviruses, oxidative stress, hypoxia.


Geroprotective effects of ethylmethylhydroxypyridine succinate in an experimental study

Author:
T.A. VORONINA

FSBI «Zakusov Institute of Pharmacology», Moscow

Summary:
Objective. To study an effect of mexidol on the life expectancy, weight, seizure response thresholds, and impaired cognitive and
motor functions during aging in male Wistar rats. Material and methods. In a long-term experiment, male Wistar rats, aged 3—26 months, were assessed for impaired cognitive functions (passive avoidance conditioned reflex test), convulsive threshold (test with pentylenetetrazole), motor deficits (tests of rotating rod and pulling on the crossbar), and life expectancy. The rats received mexidol in the form of 0,15% solution, which replaced drinking water, during two 2 month courses at the age of 18—20 and 22—24 month. A dose of mexidol consumed by the rat was 40-75 mg/kg/day. Results. In old male Wistar rats, the long-term treatment with mexidol increases the life expectancy, improves learning, preservation and reproduction of the memory trace in the passive avoidance conditioned reflex test, increases the convulsive threshold and improves muscle tone and coordination of movements that are impaired during aging. Conclusion. Mexidol increases the threshold of convulsive reaction, restores cognitive and neurological deficits that occur during aging in male Wistar rats and increases the by its ability to influence mitochondriogenesis and antioxidant properties.
Keywords: aging, mexidol, life expectancy, memory impairment, neurological deficit, convulsive threshold.


The effect of Mexidol on cerebral mitochondriogenesis at a young age and during aging

Author:
YU.I. KIROVA1, F.M. SHAKOVA1, E.L. GERMANOVA1, G.A. ROMANOVA1, T.A. VORONINA2

1 Institute of General Pathology and Pathophysiology, Moscow, Russia;

2 Zakusov Research Institute of Pharmacology, Moscow, Russia

Summary:
Objective. To study the ability of mexidol to induce cerebral mitochondriogenesis in the brain of young and aging rats. Material and methods. Expression level of marker proteins of cerebral mitochondriogenesis was evaluated during treatment with mexidol (20, 40, 100 mg/kg; 20 days; intraperitoneally) in the cerebral cortex of young (3 month) and aging (6, 9, 12, and 15 month) outbred male rats, using the Western blot analysis. Results. It has been shown for the first time that the course injections of mexidol in doses of 40 and 100 mg/kg is accompanied by dose-dependent induction of the succinate receptor SUCNR1 and protein markers of mitochondrial biogenesis: transcription coactivator PGC-1α, transcription factors (NRF1, TFAM), catalytic subunits of respiratory enzymes (NDUV2, NDUV2,cytb, COX2) and ATP synthase (ATP5A) in the cerebral cortex of young and aging outbred male rats. Mexidol-dependent overexpression of subunits of mitochondrial enzymes and PGC-1α is observed only with the course of the drug. Conclusion. The results indicate the ability of mexidol to induce cerebral mitochondriogenesis and eliminate mitochondrial dysfunction in young and aging animals and, thus, exert an effect on one of the key pathogenetic links of the development of disorders in aging and neurodegenerative diseases.
Keywords: aging, mitochondrial dysfunction, mexidol, succinate receptor, cerebral mitochondriogenesis, transcriptional coactivator PGC-1α, respiratory enzyme subunits, rats, Western blot analysis.


Effect of mexidol on physical and mental performance under stressogenic conditions in experiment

Author:
I.G. KAPITSA, E.A. IVANOVA, T.A. VORONINA

FSBI «Zakusov Institute of Pharmacology», Moscow

Summary:
Resume. The effect of Mexidol on physical performance of mice under the extreme conditions of the weight-loaded forced swim test and on the mental performance of rats under the conditions of a neurosis-like state caused by a functional disturbance of a defensive instrumental conditioned active avoidance reflex was studied. A single dose (50 and 100 mg/kg) or a subchronic regimen (100 mg/kg) of Mexidol administered intrapertoneally enhances the physical performance of mice similarly to mildronate (100 mg/kg). Mexidol improves the rate of operant conditioning, the preservation of the memory trace and its restoration after single or multiple instances of disruption of the conditioned active avoidance reflex, and its effect does not differ from the effect of the comparison drug piracetam (300 mg/kg).
Keywords: performance; learning; memory; functional disturbance.


Effect of mexidol on physical working efficiency and level of lactat in blood rats in conditions of light desynhronizes

Author:
T.A. ZAMOSHCHINA, A.A. GOSTYUKHINA, K.V. ZAITSEV, M.V. SVETLIK, O.B. ZHUKOVA

Federal state budgetary institution «Siberian Federal science-clinical center of Federal medicobio-logical agency», Seversk, Russia; Siberian
State Medical University SSMU, Tomsk, Russia

Summary:
Objective. To study an effect of mexidol on the performance of rats after light or dark deprivations in the swimming test with a load and to evaluate the state of glycolytic processes under these conditions. Material and methods. The experiment was carried out in the spring on 70 Wistar male rats. Three groups (30 animals) were in natural light conditions. One of them was not affected. The other two groups were subjected to exercise and 30 minutes before it either saline or mexidol was administered intramuscularly. Four other groups (40 animals) for 10 days were under conditions of dark or light deprivation prior to the presentation of physical activity and received either saline or mexidol before the test after deprivation was canceled. A forced swimming test with an additional load, which was presented to animals every day at 10—11 am for five days in a row, was used as a model of physical activity. The level of lactate was determined by colorimetric method. Results and conclusion. Mexidol increased the performance of rats in the swimming test, both under natural lighting conditions and with light desynchronization, contributed to the formation of cross adaptation to physical activity under natural lighting conditions and prolonged this state under conditions of light deprivation, did not change the content of lactate in the blood of rats after exercise in natural lighting conditions and dark deprivation and prevented its rise after light deprivation.

Keywords: mexidol, light and dark deprivation, working capacity, lactate.


Influence of mexidol and hemisuccinate 2-ethyl-6-methyl-3-hydroxypyridine on cerebral hemodynamics at hemorrhagic and ischemic damage of brain

Author:
I.N. KURDYUMOV1, T.S. GAN,SHINA1, D.V. MASLENNIKOV1, E.V. KURZA1, A.A. GORBUNOV1,2, A.I. TURILOVA1 and R.S. MIRZOYAN1

1 V.V. Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, ul. Baltiiskaya 8, Moscow. 125315 Russia

2 I.M. Sechenov First Moscow State Medical University (Sechenov University), ul. Trubetskaya 8, Moscow, 119881 Russia

Summary:
Comparative study of the effect of mexidol and hemisuccinate 2-ethyl-6-methyl-3-hydroxypyridine on the cerebral circulation of rats under conditions of hemorrhagic and ischemic brain lesions revealed significant differences in their cerebrovascular effects. Mexidol at a dose of 200 mg/kg i.v. better improves the local cerebral blood flow in modeling ischemia as compared to hemorrhagic brain damage. Hemisuccinate 2-ethyl-6-methyl-3-hydroxypyridine at a dose of 50 mg/kg better enhances the local blood supply to the cerebral cortex under conditions of hemorrhagic brain damage as compared to ischemic damage, since its cerebrovascular effect during cerebral ischemia occurs in a dose of 100 mg/kg. The mechanism of cerebrovascular anti-ischemic effect of 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate is mediated by GABAa receptors of the brain vessels, since bicuculline eliminates this effect.

Keywords: mexidol; hemisuccinate 2-ethyl-6-methyl-3-hydroxypyridine; bicuculline; cerebral circulation; hemorrhagic stroke model; global transient ischemia.


An effect of mexidol on the expression of the transcription factor Nrf2 in cerebral cortex in ischemia

Author:
E.N. YAKUSHEVA, P.YU. MYLNIKOV, I.V. CHERNYKH, A.V. SHCHULKIN.
Ryazan State Medical University, Ryazan, Russia.

Summary:
Objective. To study an effect of the antioxidant and antihypoxant mexidol (ethylmethylhydroxypyridine succinate) on the transcription factor Nrf2 expression in neuronal nucleis of frontal cortex cells autor the common carotid artery unilateral occlusion. Material and methods. The study was performed on 64 male Wistar rats. The Nrf2 expression was determined immunohistochemically. Results. Single intraperitoneal mexidol (120 mg/kg b.w.) infusion and oral (100 mg/kg p.w. thrice a day for 14 days) administration of mexidol did not affect Nrf2 expression. Unilateral common carotid artery occlusion led to the increase in Nrf2 expression 4 h and 5 days after occlusion. Oral administration of mexidol in dose of 100 mg/kg b.w. thrice a day for 14 days before and after ischemia increased Nrf2 expression on the 4th h and on the 12th day in comparison with intact animals. Nrf2 expression was higher after 4 h and 12 days in comparison with the control occlusion group. Conclusion. Mexidol increases Nrf2 expression in the frontal cortex of rats not under normal conditions but in common carotid artery unilateral occlusion.

Keywords: mexidol, Nrf2, ethylmethylhydroxypyridine succinate, ischemia, occlusion, common carotid artery.


The study of the neuroprotective effect of mexidol on the cellular model of glutamate stress

Author:
O.A. GROMOVA, I.YU. TORSHIN, E.V. STELMASHUK, O.P. ALEXANDROVA, A.V. PRONIN, I.V. GOGOLEVA, L.G. HASPEKOV
Federal Research Center «Informatics and Cybernetics», RAS, Moscow, Russia; Scientific Center of Neurology, Moscow, Russia; Ivanovo State Medical Academy of the Ministry of Health of Russia, Ivanovo, Russia

Summary:
Purpose of the study. Study of neuroprotective properties of mexidol on a cellular model of glutamate stress. Material and methods. Cytological studies were carried out under the conditions of the model of glutamate stress in the culture of granular neurons of the cerebellum. Results. The addition of mexidol to the cultural medium increased the survival of neurons by 8-10% after the addition of glutamate (p<.05). The effect of mexidol was more pronounced when applied at the stage of growing the culture of neurons (5 days), when the survival of the cells in conditions of glutamate stress increased by an average of 20%. The conclusion. The results of the study confirm the direct neuroprotective effect of mexidol in the culture of neurons under the conditions of the glutamate stress.

Keywords: cellular stress, excitotoxicity, glutamate, mexidol.


Comparative chemoreactome analysis of mexidol

Author:
I.YU. TORSHIN, O.A. GROMOVA, I.S. SARDARYAN, L.E. FEDOTOVA
Moscow Institute of Physics and Technology, Dolgoprudny. Russia; Ivanovo State Medical Academy of the RF Ministry of Health, Ivanovo, Russia

Summary:
Objective. To compare mexidol with control molecules (choline alfoscerate, piracetam, glycine, semax) using chemoreactome analysis. Material and methods. The chemical structure of mexidol was compared to molecule metabolites extracted from the Human Metabolome Database (HMDB) and a drug database. More than 40 000 of metabolites from HMDB were used as a model of human metabolome. Results and conclusion. The chemoreactome analysis showed that mexidol may be (1) an agonist of acetylcholine and GABA-A receptors; (2) an anti-inflammatory agent, the effects of which are carried out by inhibiting the synthesis of pro-inflammatory prostaglandins; (3) a neurotrophic agent with neuroprotective properties; (4) a coagulation inhibitor; (5) a diabetes medication and (6) a hypolipidemic agent. Compared to «control» molecules, mexidol has a more pronounced safety profile (a lower impact on serotonin, dopamine and adrenergic receptors, a lesser degree of interaction with the potassium channels of the heart, MAO and P450 cytochromes). The results of modeling allow to specify the mechanisms of action of mexidol at the molecular level.

Keywords: mexidol, neuroprotection, chemoreactome analysis, chemoinformatics, forecasting.


Mexidol effect on the factor induced by hypoxia HIF-1α expression in the rat cerebral cortex in its ischemia

Author:
E.N. YAKUSHEVA, P.YU. MYLNIKOV, I.V. CHERNYKH, A.V. SHCHULKIN.
Pavlov Ryazan State Medical University, Ryazan, Russia.

Summary:
The aim of the research – to study the Mexidol (ethylmethylhydroxypyridine succinate) effect on the factor induced by hypoxia (HIF-1α) expression in the frontal cortex of the brain in its ischemia. Material and methods. The work was performed on the 64 male Wistar rats. The expression of HIF-1α was determined immunohistochemically. Results and discussion. It is determined that single intraperitoneal administration of Mexidol at a dose 120 mg/kg and oral administration at a dose 100 mg/kg three times a day for 14 days is not affected the expression of HIF-1α. Unilateral occlusion of the common carotid artery increases the expression of HIF-1α at 4 hours after the occlusion. Oral administration of Mexidol at a dose 100 mg/kg three times a day for 14 days before and after ischemia increases the expression of HIF-1α after 4 and 12 hours in comparison with the norm, on the 5th day in comparison with occlusion control. Thus, it has been established that Mexidol increases the expression of HIF-1α in the frontal cortex of rat brain not under normal conditions, but in unilateral occlusion of the common carotid artery.

Keywords: mexidol, ethylmethylhydroxypyridine succinate, ischemia, occlusion of common carotid artery.