Alkaloids of Peganum harmala L. and their Pharmacological Activity

Peganum harmala L. contains 17 alkaloids of quinazoline and indole structure types. Of these, harmaline, harmine, harmalol and L-peganin (vazicin) are pharmacologically active. It was established that of the alkaloids contained in the seeds, 50-95% is dominated by harmaline, harmine is dominated in the roots (67-74% of the total of extractive substances), and in the aerial part, the main mass is peganin (up to 78% of the total of alkaloids). Beta-carboline alkaloids of Peganum harmala L. inhibit monoamine oxidase, thereby exerting a neuroprotective effect. This article is devoted to the results of studies of the neurotropic action of harmine hydrochloride, when compared with the activity of the reference drug “Amitriptyline”. It was shown that the use of harmine hydrochloride helps to reduce the level of anxiety in animals under conditions of experimental psychoemotional chronic stress with prolonged administration. In the study of acute and chronic toxicity, it was determined that harmine hydrochloride belongs to the category of moderately toxic substances (hazard class II). According to the results of molecular docking, the presence of strong bonds in harmine hydrochloride with the serotonin 5-HT2C receptor, dopamine D2 receptor, as well as monoamine oxidase A and B was revealed, which indicates the implementation of the mechanism of neurotropic action of harmine hydrochloride at the level of synaptic neurotransmission of monoamines (dopamine, serotonin and others). It was also established that harmine hydrochloride eliminates haloperidol-induced catalepsy in rats, reduces oligokinesia and rigidity in the Parkinson’s test, has antihypoxic activity in the hypobaric hypoxia test, and exhibits pronounced antidepressant activity in the Porsolt’s test. In the course of the study of pharmacokinetics and bioavailability, it was revealed that with the administration of harmine hydrochloride, the quantitative content is quickly achieved and the concentration of the active substance in the blood significantly increases. The relative bioavailability of harmine hydrochloride is 112.7%.

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).

Analysis of the relationship between the predicted biological activity and the chemical structure of S-derivatives of 5-(5-bromofuran-2-yl)-4R-1,2,4-triazole-3-thiols

1,2,4-Triazole derivatives are actively used as components in the development of new drugs, plant protection products, polymeric materials, anti-corrosion agents and etc. Chemical modeling of substituted 1,2,4-triazoles due to the introduction of different pharmacophores into the structure is very popular among scientists in various fields. Today it is known that some S-derivatives of 5-(5-bromofuran-2-yl)-4R-1,2,4-triazole-3-thiols have antimicrobial activity. The aim of the work is to analyze the relationships between the predicted biological activity and the chemical structure of S-derivatives of 5-(5-bromofuran-2-yl) -4R-1,2,4-triazole-3-thiols. Materials and methods. Virtual screening of compounds was performed using the computer program PASS (Prediction of activity spectra for substances). The results of the forecast were issued in the form of a list of names of probable types of activity with estimates of the probabilities of presence (Pa) and absence of each activity (Pi), which had values from 0 to 1. Results. Analyzing the prediction of biological activity on protein targets from the group of enzymes, we can said that derivatives of 5-(5-bromofuran-2-yl)-4R-1,2,4-triazole-3-thiols were active in the group of oxyreductases (Glutathione reductase, mitochondrial; Cyclooxygenase-2; Hypoxia-inducible factor prolyl hydroxylase 2), which catalyzed oxidation reactions, the transfer of electrons from one molecule (reducer, electron donor) to another (oxidant, electron acceptor). These compounds can demonstrate antioxidant, antihypoxic activity. Conclusions. The conducted forecast of biological activity revealed that derivatives of 5-(5-bromofuran-2-yl)-4R-1,2,4-triazole-3-thiols are the most active and there is a probability to show antitumor, antiviral, antibacterial, diuretic, actoprotective, and antioxidant activity.

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.

THE ANTIHYPOXIC ACTIVITY OF SIBERIAN FIR ESSENTIAL OIL FRACTIONS

The component composition and antihypoxic activity of Siberian fir (Abies sibirica) essential oil fractions were researched. The foliage of Siberian fir, collected on the territory of the Ilyinsky district of the Perm region in a dark coniferous forest was the raw material for obtaining the essential oil. Samples for the research were collected in December 2018 from trees 40–50 years old. The essential oil was obtained with the Clevenger apparatus. Determination of the component composition of Siberian fir essential oil fractions was made by using chromatography-mass-spectrometry. Experiments for determination of antihypoxic activity of Siberian fir essential oil fractions were made on a hypoxic hypoxia model with hypercapnia. According to the results of the research, it was found that the first fraction is more saturated with monoterpene compounds, but the proportion of sesquiterpenoids increases in following fractions. The main components of all fir oil fractions are: bornylacetate, limonene, ∆3-carene, karyophyllene. It was found that the fractions 1 and 2 have the highest antihypoxic activity in comparison with the reference sample. For further research, we offer fraction 1, because it contains the high level of bornylacetate, and the lowest content of ∆3-carene, which inhibits the ubiquinol cytochrome-C reductase complex, interrupting mitochondrial and cell respiration.

Search for the optimal mass profile of neuropeptides for the implementation of antihypoxic and activating actions

In this study, the dependence of the pharmacological effects of neurotropic peptides of natural and synthetic origin on their structure was studied in laboratory rats. First, the study of the relative molecular profiles of peptide complexes was carried out using HPLC (gel-penetrating chromatography) with an internal standard. Then peptide complexes were administered to animals rectal and verified their biological activity on two independent models antihypoxic activity (method of altitude the lift timing of the animal's life at a critical height) and the model of assessment of physical performance (time of forced swim test of animals with a load of 10% of the body weight to failure). The obtained data on biological activity (increase) were compared with the features of the structure of peptides. To assess the effect of drug doses on their activity, a single-factor analysis of variance was performed. It has been shown that antihypoxic activity and performance stimulation are more or less inherent in all the studied peptide preparations, and are dose-dependent and related to the features of the molecular mass distribution of peptide components. It was also found that the specific antihypoxic activity of peptide preparations from brain tissues is associated with components having a mass range from 5 to 10 kDa. The optimal proportions of the peptide components for the implementation of biological activity by mass ranges were determined. In addition, the chromatographic characteristics (molecular weight distribution over mass ranges) of natural neuropeptide complexes can be used to predict the severity of their biological effects.

Magnesium Sulfate Attenuates Lethality and Oxidative Damage Induced by Different Models of Hypoxia in Mice

Mg2+ is an important cation in our body. It is an essential cofactor for many enzymes. Despite many works, nothing is known about the protective effects of MgSO4 against hypoxia-induced lethality and oxidative damage in brain mitochondria. In this study, antihypoxic and antioxidative activities of MgSO4 were evaluated by three experimental models of induced hypoxia (asphyctic, haemic, and circulatory) in mice. Mitochondria protective effects of MgSO4 were evaluated in mouse brain after induction of different models of hypoxia. Antihypoxic activity was especially pronounced in asphyctic hypoxia, where MgSO4 at dose 600 mg/kg showed the same activity as phenytoin, which used as a positive control ( P < 0.001 ). In the haemic model, MgSO4 at all used doses significantly prolonged latency of death. In circulatory hypoxia, MgSO4 (600 mg/kg) doubles the survival time. MgSO4 significantly decreased lipid peroxidation and protein carbonyl and improved mitochondrial function and glutathione content in brain mitochondria compared to the control groups. The results obtained in this study showed that MgSO4 administration has protective effects against lethality induced by different models of hypoxia and improves brain mitochondria oxidative damage.

Antihypoxic activity of the VMA-10-18 derivate under hypobaric hypoxia in mice

The present study was carried out to evaluate the effect of a new derivative VMA-10-18 (10 mg/kg) on the resistance of mice to acute hypobaric hypoxia. It was confirmed that the studied derivative contributes to an increase in the life time on the lethal test site by 2,7 times (p <0,05) compared with the control group of animals and exceeds the strength of the effect of the reference drug Metaprot by 1,2 (p <0,05).