Membranotropic effect of phytodrugs

МЕМБРАНОТРОПНА ДІЯ ФІТОПРЕПАРАТІВ

Актуальність. У статті на підставі власних досліджень і джерел літератури наведені дані щодо впливу лікарських засобів рослинного походження, насамперед на іонні канали. Мембранотропна дія також пов'язана з рецепторами, ферментами, сигнальними системами. Разом із тим роботи останніх років пов'язують вплив рослинних препаратів саме на іонні канали, тому першочергово у статті акцентується увага на дії фітопрепаратів передусім на іонні канали, різниці їх структури і значенні в механізмі дії фітопрепаратів. Саме сучасну фармакотерапію неврологічних, серцево-судинних та інших хвороб часто доповнюють фітозасобами завдяки їх здатності підвищувати ефективність традиційної фармакотерапії і малої токсичності та вартості.

Мета роботи - показати мембранотропну дію фітопрепаратів на підставі їх впливу на іонні канали.

Методи дослідження. Був проведений аналіз вітчизняної і зарубіжної літератури, відомості з друкованих та інтер- нет-видань. Визначені властивості й види калієвих, кальцієвих, натрієвих каналів.

Результати дослідження. Показано вплив фітопрепаратів на ці канали, зв'язок з їх фармакологічними властивостями. Можливості рослинних препаратів впливати на калієві, кальцієві, натрієві канали свідчать про мембранотропну дію препаратів.

Висновки. Фітопрепарати, як і синтетичні засоби, можуть володіти мембранотропним впливом, що пояснює їх кардіо- та нейротропну дію. Мембранотропна дія цих засобів обумовлена здебільшого впливом на калієві та кальцієві канали.

Ключові слова: фітопрепарати, калієві, кальцієві, натрієві канали, мембранотропна дія.

Aktuality

herbal medicines membranotropic

The membranotropic action of the drugs largely underlies their specific activity, neurotropic, cardiotropic and other types of action. during its implementation of a specific effect, attention was paid to the role of ion channels of messenger enzymes and certain signaling systems that started the reaction (Vislobokov et al., 2010).

Study purpose. Membranotropic activity is associated with thiolde components of the sulfide system and nitric oxide (Belenichev et al., 2020), revealing the pharmacological properties of metabolitotropic drugs, which include phytoremedies (Belenichev et al., 2020).

Research materials and methods. Analyzing the effect of most herbal drugs, attention was paid to their significant effect on potassium channels. Potassium cations have a transmembrane gradient value, most of these ion channels are potential-dependent, although there are also potential-independent forms, a certain part of potassium channels are calcium-dependent and ATP- dependent (Mamchur et al., 2016).

Research results and discussion

Potassium channels, like sodium and calcium channels, are transmembrane proteins that selectively pass potassium ions, moving along an electrochemical gradient at a certain speed. Potassium channels have 4 alpha subunits and specialized formation segments:

- a pore filled with water and permeable to potassium;

- a selectivity filter that allows only potassium;

- the permeation mechanism, which switches to the open and closed state in response to changes in the membrane potential or to ligand binding.

In the structure of the channel there are areas responsible for selectivity, opening of the channel. Knowing the structure of the channels allows you to find means that allow you to use potassium channels more efficiently. There are many existing codes for potassium channels, because potassium channels are also found in mitochondria. These channels have a main subunit with S5-S6 segments or their analogues, which indicate ion selectivity, interaction with drugs (Pogilova et al., 2016).

Separately, three types of potassium channels are distinguished:

- channels with six transmembrane segments and one pore that vary genetically. A family of calcium- dependent channels related to the genes KCNA (Shaker), KCNB (Shab), KCNC (Shaker), KCND (Shal), hERG with the human gene, Ca²+-activated K+ channels and depolarization-activated KCNQ channels;

- channels with two transmembrane fragments and one pore - K⁺ channels of internal rectification, consisting of an alpha subunit with two transmembrane segments M1 and M2 and a transforming linker;

- canals with four segments and two pores.

The channel filter contains carboxyl atoms of amino acids and passes potassium ions, but does not pass sodium ions because the pore diameter is too wide for them to provide energetic hydration of sodium ions. The selectivity of potassium channels, wherever they are, are located similarly. It is the search for pharmacological agents that allows us to selectively find drugs that correct the work of potassium channels, relative potentials of dependent potassium channels linked to genes. This applies to channels with six transmembrane elements and one pore.

Potential-controlled K⁺ channels are distinguished by their functions, among which the main group are channels of delayed (outgoing) rectification, inward rectification, Ca²+^- sensitive, K+ ATP-sensitive, K⁺ channels, Na⁺ activated R⁺ channels sensitive to changes in cell volume, K⁺ channels of the type And receptor-controlled potassium channels.

Potassium channels with heavy intermediate and low conductance are distinguished. there are mechanosensitive channels that open upon mechanical stimulation (Cukkemane et al., 2011).

They are believed to consist of four subunits that are in a tegrammer. The outer mouth of the P-cycle and adjacent residues of the S5-S6 segments are the binding site for toxins and blockers of K⁺ channels located near the pore and responsible for inactivation.

The antiarrhythmic activity of the liquid extract and tincture of hawthorn and dog nettle, along with other aspects of their effects, is known from herbal drugs. The antiarrhythmic activity of these agents is based on the blockade of potassium channels (Karomatov et al., 2017).

The medicinal properties of these herbal drugs were determined during the creation of the drug Kratal, which, in addition to extracts of hawthorn and dog nettle, included taurine - Kratal has antianginal, cardio- and neuroprotective effects (Gorchakova, 2001).

In Chinese medicine, there are a number of herbal drugs that can block potassium channels and have an antihypertensive effect. These include phytodrugs of red beetroot, hawthorn root, bitter gourd, viburnum berries, and calendula flowers. These herbal drugs not only lowered blood pressure but also improved arterial blood circulation (Cao et al., 2021). Chinese herbal drugs, which have cardiotonic effects and some antiarrhythmic effects due to their effects on potassium channels, were tested for cardiotoxicity by their effects on Herg receptors. These drugs had no cardiotoxicity by affecting the Herg gene (Choi et al., 2019).

Ferulin plant oil has a vasodilatory effect due to the blockade of potassium channels, which was demonstrated in experiments on isolated rabbit aorta (Esmaeili et al., 2020).

When studying the effect on ATP-dependent potassium channels, there are now reports about herbal remedies that can have a hypoglycemic effect and that can be used in the complex treatment of diabetes. Among these plants, horsetail leaves, nettles, dandelions, blueberries, lingonberries, bean pods, almonds, hazelnuts, and others are noted. drugs from these plants inhibit the absorption of glucose in the intestines, increase insulin reserves. Their mechanism of action is similar to the mechanism of action of sulfonamide derivatives and is associated with the blockade of ATP-dependent potassium channels, i.e., it is implemented membranotropically (Al Kury, 2023).

Many of these herbal drugs also have a beneficial effect on the digestive tract. Flavonoids have long been used in Chinese medicine to treat hypertension (Cao et al., 2021). The benefit of including flavonoids in the complex treatment of hypertension has been proven by clinical and clinical studies.

The inclusion of phytodrugs in the treatment regimen for hypertension in the elderly was especially useful. Very often, these agents had a positive effect on the function of the kidneys, the digestive tract and the central nervous system. Some of these phytoremedies simultaneously blocked sodium channels, and sometimes calcium channels, which expands the indications for use in medical practice. Ferulin oil was obtained from ferula plants, which was predicted to have a vasodilating effect. The complex herbal drug with the conventional name ferulin, due to the blockade of potassium channels, has a vasodilating effect, which was confirmed in experiments on an isolated rat aorta (Esmaeili et al., 2020).

In order to check the possibility of cardiotoxicity of herbal remedies used in cardiology, experiments were conducted on kidney tissues of embryos in which the herg gene, which is associated with potassium channels, was identified. In these experiments, 52 herbal drugs were tested. The absence of cardiotoxicity in cardiac herbal drugs was established, because they did not affect the herg gene and did not change the permeability of potassium channels (Choi et al., 2019).

Medicinal products obtained from sage, vaginal mustard, and St. John's wort, from which medicines are prepared that affect Ca, K, Na channels and fast and slow current receptors (Huang et al., 2019). Extracts from hawthorn fruits, bitter gourd, and lettuce were compared for potassium channel blockade and blood pressure. It has been shown that in equivalent concentrations they can have a comparable antihypertensive effect (Jitendra Joshi & Ashok Shelke, 2021).

Phytodrugs in food affect both potassium channels and TRPV receptors, which regulate body weight and blood pressure. Later, a correlation with the effect on these channels of onion terminals and common wort is shown, which means the elimination of diseases that block potassium channels and explains the effect of herbal medicines in a new way (Herbrechter et al., 2020).

It is interesting to note that herbal drugs with a calming effect on the central nervous system can simultaneously block potassium channels and NMDA receptors, which is observed when using peony root, dog nettle, rosehip fruits, sage grass and fennel seeds (Lin & Hsieh, 2021).

The herbal remedy of cilantro fruit blocks potassium channels of the KCNQ family and has efficacy not only in hypertension but also in encephalopathy (Manville & Abbott, 2019).

A herbal drug from Sophora root can block potassium channels and simultaneously increase NO levels, which explains its value in the treatment of hypertension and coronary heart disease (Manville et al., 2019).

Fern drugs also increase NO and heat shock proteins by blocking potassium channels. In addition, during inflammation, the drug reduces tumor necrosis factor а and pro-inflammatory interleukins (Mao et al., 2019).

In recent years, considerable attention has been paid to fennel and ginger phytoremedies, which have a complex mechanism of action, including the blockade of potassium channels, the effect on the content of NO and ATP, which are prescribed for hypertension, diabetes, and convulsions (Redford & Abbott, 2022).

Special importance is attached to ATP-dependent potassium channels, because herbal drugs that act on these channels can be prescribed for diabetes. Their mechanism of action is similar to glimepiride and they can be prescribed together with it. The phytodrug berberine has a similar effect.

A randomized, placebo-controlled trial was conducted. One group of patients was given barberine, the other a placebo. Berberine is a glucose-dependent insulin agent for the treatment of diabetes, but does not cause hypoglycemia, although it is less sensitive to K-sensitive channels and membranes (Zhao et al., 2021).

In recent years, the transmembrane effect of plants has been associated with the effect on calcium channels. Calcium ions in nerve cells and in the myocardium play a significant role. They participate in the initiation of the action potential, regulate rhythmic activity, gene expression, and, as secondary messengers, participate in the regulation of intracellular biochemical processes, promote the release of neurotransmitters in presynaptic membranes. Potential-dependent Ca²+ channels identified in the membrane of cells with electrical excitability (cardiac muscle, smooth muscle, neurons, endocrine cells). Therefore, potential-dependent and Ca^2- dependent inactivation are distinguished, which depends on the calcium content during the depolarizing pulse. Calcium channels can be blocked by cationic drugs and plant compounds (Timmermann et al., 2001). They are well permeable to divalent and not monovalent cations.

The selective dimer of Ca²⁺ channels can contain two areas of communication with cations - external and internal. Calmodulin can be in the structure of a calcium channel, a similar part of the structure of calcium channels is similar to sodium channels and has five protein subunits: a1, a2, 5, y. It is the a1 subunit that carries more functions. Calcium channels are divided into low-threshold (LVA), in which channel activation develops above the resting potential, and high-threshold (HVA), when activation develops above the action potential (Pahlavan et al., 2018).

Hypobaric hypoxia is more common in climbers and high-altitude climbers and has the ability to impair cognitive function. Ginkgo Biloba is a herbal remedy used for various diseases. It improves cognitive functions, reduces stress and is widely used as a medicine. It is indicated for neurological disorders. At the same time, the functions of the hippocampus improve, which is confirmed by the study of molecular mechanisms and morphology.

Ginkgo biloba modulates the activity of calcium- activated potassium channels, reducing glutamate excitotoxicity and apoptosis of some synaptic pathways. The drug can affect the calcium conductivity of activated potassium channels, activates extracellular signals of the regulation of kinase II and CAMP bonds, sexuterpene lactones - leucosine and achinine, which establishes their leading role in the implementation of the antispasmodic effect of the extract (Arias-Duran et al., 2020).

Tryptophan plays a role in the permeability of calcium channels, the activity of AMP, the interaction of the activity of peptides. That is, tryptophan actively interacts even with negatively charged polysaccharide lipids and other membrane components. Thanks to it, membranotropic ones are determined peptides that play a role in bactericidal action (Khemaissa et al., 2022).

Conclusion

References

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