PHARMACOLOGICAL EFFECT OF BIOLOGICALLY ACTIVE COMPOUNDS OF THE LEVISTICUM OFFICINALE W.D.J. KOCH

ФАРМАКОЛОГИЧЕСКОЕ ДЕЙСТВИЕ БИОЛОГИЧЕСКИ АКТИВНЫХ ВЕЩЕСТВ ЛЮБИСТОКА ЛЕКАРСТВЕННОГО

Научная статья

Кубасова Е.Д.^1, *, Корельская Г.В.², Черных И.В.³, Крылов И.А.⁴, Кубасов Р.В.⁵

¹ ORCID: 0000-0001-9683-7814;

² ORCID: 0000-0003-4236-1966;

³ ORCID: 0000-0002-5618-7607;

⁴ ORCID: 0000-0003-3042-4229;

⁵ ORCID: 0000-0003-1698-6479;

^1,2,4,5 Северный государственный медицинский университет, Архангельск, Россия;

³ Рязанский государственный медицинский университет имени академика И.П. Павлова, Рязань, Россия

* Корреспондирующий автор (lapkino[at]mail.ru)

Аннотация

Среди растений семейства сельдерейных (Apiaceae), которые применяются в народной медицине, одним из перспективных является Любисток лекарственный (Levisticum officinale W.D.J. Koch), поскольку он содержит в своем составе различные фитохимические соединения. Биологически активные веществ определены в различных частях любистока. Их фармакологические свойства обусловили включение лекарственного сырья в ряд Европейских Фармакопей. Фталиды в эфирных маслах любистока представлены в наибольшем количестве. Они, имеют антибактериальный, противогрибковый, противовоспалительный, цитопротекторный и антиоксидантный эффект. Кроме того, характеризуются гастро- гепато- и нейропротекторными свойствами. Флавоноиды обладают цитотоксическим действием в отношении онкологических клеток; также изучено их нейропротекторное и антитромбическое действие; положительно эффект на репродуктивную систему. Известен антиноцицептивный и антигипертензивный эффекты хлорогеновых кислот любистока лекарственного. Полиацетилены обладают антиагрегационным действием в отношении тромбоцитов; также они могут подавлять рост опухолевых клеток. Наконец, алкалоиды, извлеченные из растительного сырья любистока (тетраметилпиразин и его производные), обладают антитромбоцитарным, противовоспалительным и нейропротекторным эффектами. Таким образом, широкий спектр фармакологического действия биоактивных соединений любистока лекарственного делает его перспективным к использованию в фармацевтической индустрии.

Ключевые слова: лекарственное растение, Любисток лекарственный, биологически активные вещества, фармакологические свойства.

PHARMACOLOGICAL EFFECT OF BIOLOGICALLY ACTIVE COMPOUNDS OF THE LEVISTICUM OFFICINALE W.D.J. KOCH

Research article

Kubasova E.D.^1, *, Korelskaya G.V.², Chernykh I.V.³, Krylov I.A.⁴, Kubasov R.V.⁵

¹ ORCID: 0000-0001-9683-7814;

² ORCID: 0000-0003-4236-1966;

³ ORCID: 0000-0002-5618-7607;

⁴ ORCID: 0000-0003-3042-4229;

⁵ ORCID: 0000-0003-1698-6479;

^{1, 2, 4, 5} Northern State Medical University, Archangelsk, Russia;

³ Ryazan State Medical University named after academician I.P. Pavlov, Ryazan, Russia

* Corresponding author (lapkino[at]mail.ru)

Abstract

Among the plants of the celery family (apiaceae), which are used in folk medicine, one of the most promising is the Levisticum officinale W.D.J. Koch, due to it contains various phytochemical compounds in its composition. The biologically active substances were detected in various parts of Levisticum officinale W.D.J. Koch. Their pharmacological properties have led to the adding of medicinal raw materials in a number of European Pharmacopoeias. Phthalides in the essential oils of Levisticum officinale W.D.J. Koch are represented in the maximum quantity. They have antibacterial, antifungal, anti-inflammatory, cytoprotective and antioxidant effects. In addition, they are characterized by gastro-hepatoprotective and neuroprotective properties. Flavonoids have cytotoxic effects against cancer cells; their neuroprotective and antithrombic effects have also been studied; a positive effect on the reproductive system. Antinociceptive and antihypertensive effects of chlorogenic acids of the Levisticum officinale W.D.J. Koch are known. Polyacetylenes have an antiaggregational effect of platelets; they can also inhibit the growth of tumor cells. Finally, alkaloids extracted from the plant raw materials of Levisticum officinale W.D.J. Koch (tetramethylpyrazine and its derivatives) have antiplatelet, anti-inflammatory and neuroprotective effects. Thus, a wide range of pharmacological action of bioactive compounds of the Levisticum officinale W.D.J. Koch makes it promising for use in the pharmaceutical industry.

Keywords: medicinal plant, Levisticum officinale W.D.J. Koch, biologically active compounds, pharmacological effect.

Levisticum officinale W.D.J. Koch is a perennial cold-resistant herbaceous plant of the Umbelliferae or Apiaceae family [1], [2]. Its natural habitat is Iran and Afghanistan, it is widely distributed in the Mediterranean, in mountainous areas of Southern Europe and North America. It grows everywhere in Ukraine, industrial plantations of Levisticum officinale W.D.J. Koch, as a medicinal plant, are available in the Poltava region. The plant is cultivated in many European countries (Germany, Hungary, the Czech Republic, Poland, etc.), including Russia [3].

Due to the pharmacological properties of biologically active substances contained in various parts of Levisticum officinale W.D.J. Koch, this plant is increasingly used in medical practice, and as a medicinal raw material is included in a number of European Pharmacopoeias [4].

Phthalides, as one of the main groups of natural compounds contained in Levisticum officinale W.D.J. Koch essential oils, demonstrates various biological activity, including antibacterial, antifungal, insecticidal, cytotoxic, anti-inflammatory effects [5]. Some monomeric phthalides are able to minimize certain neurological diseases, including stroke, Alzheimer's disease and Parkinson's disease [6]. In vivo and in vitro models have shown that dimeric phthalides can exhibit sedative and antispasmodic properties. Thus, ligustilide, as a representative of dimeric phthalide, has anti-inflammatory, antioxidant and anti-apoptotic effects. Experimentally on rats with diabetic nephropathy, it was found that ligustilide loosens podocyte damage and has a protective effect on kidney function [7]. At the same time, in an experimental model of stomach damage caused by ethanol in rats, it was proved that ligustilide at a dose of 10 mg/kg has gastroprotective activity. In parallel, the anti-ulcer activity of this compound depends on the participation of endogenous non-protein SH-groups and prostaglandins [8]. Z-ligustilide also demonstrates antitumor antithrombic effects and has a positive effect in neurological disorders [9].

In the work of R.M. Sprea et al. it is noted that the phenolic compounds contained in Levisticum officinale W.D.J. Koch have antioxidant properties. They also have bacteriostatic activity, especially against gram-positive bacteria. The use of Levisticum officinale W.D.J. Koch decoction containing phenolic compounds showed cytotoxicity against the hepatocellular carcinoma (HepG2) tumor cell line [10]. Water-alcohol extracts of Levisticum officinale W.D.J. Koch also showed antiproliferative and apoptotic activity in the cell lines of breast tumor cells, which is also possibly due to the presence of phenolic compounds in the extract [11]. It was investigated the effect of the water-alcohol extract of Levisticum officinale W.D.J. Koch on the synthesis of steroid hormones ln vitro. As a result, it was revealed the presence of concentration-dependent changes in steroidogenesis, membrane integrity, cell viability and intercellular communication of Leydig cells. Smaller doses had a positive effect on cellular parameters, and higher doses (150-300 mcg/ml) stimulated toxic effects mediated by a decrease in membrane viability and inhibition of intercellular connection through gap junctions in Leydig cells. These effects are associated with the influence of phenolic and polyphenolic compounds contained in the extract of Levisticum officinale W.D.J. Koch, the dominant of which were cinaroside, kemferol, rutin, chlorogenic and neochlorogenic acids [12]. Similar results were obtained in the study of the effect of biologically active substances in the extract of Levisticum officinale W.D.J. Koch on the mobility of sperm bulls, where experimental data confirm the potential antioxidant effect of lower doses of the extract, and therefore a positive effect on reproductive function [13].

It is known that chlorogenic, caffeic and ferulic acids extracted from Levisticum officinale W.D.J. Koch have antioxidant properties, and a powerful antioxidant effect belongs to rosemary acid [14]. In animal studies, chlorogenic acid has been found to increase insulin sensitivity and improve glucose tolerance and lipid metabolism [15]. Ferulic acid has an antihypertensive effect, reduces the risk of type II diabetes, obesity, Alzheimer's disease, eclampsia and stroke. Rosemary acid has an anti-apoptotic and anti-inflammatory effect and may play an important role in antinociceptive properties [16].

Luteolin, as a representative of the flavonoid class, in addition to its antioxidant effect, has anti-inflammatory properties. Mentofuran contained in the stems of Levisticum officinale W.D.J. Koch is closely related to the antioxidant effect, which is due to the activity of radical trapping. Research by N. Ghaedi et al. was shown that the water-alcohol extract obtained from the stems of Levisticum officinale W.D.J. Koch and containing flavonoids - luteolin and quercetin, rosemary, caffeic and hexanoic acids have the greatest inhibitory ability of α-amylase and can lead to a pronounced anti-dyslipidemic effect [14]. Water-alcohol extracts from the roots of Levisticum officinale W.D.J. Koch have the ability to cause the killing of leukemic cells and inhibit the growth of prostate tumor cells in the PC3 and DU145 lines. It is assumed that this effect is associated with the presence of polyacetylenes in the extract – falcarinol and falcarindiol. There is evidence that extracts containing high concentrations of falcarinol have, as a rule, the greatest inhibitory effect on the growth of cancer cells compared with its group representative – falcarindiol [17].

Many researchers have noted that the bioactivity of falcarinol and falcarindiol extracted from Levisticum officinale W.D.J. Koch extends to antiplatelet aggregation, cytotoxic and anti-inflammatory, serotonergic, antimycobacterial activity [18].

In the work of S. Sertel et al. cytotoxicity of essential oil from the leaves of Levisticum officinale W.D.J. Koch is noted in relation to squamous cell carcinoma cells of the head and neck, in which the main fraction consists of monoterpenes, the most common of them was α-terpinyl acetate (48.15%). At the same time, no falcarinol was found in the composition of the essential oil. The authors did not find any supporting data in the literature regarding the anticancer activity of α-terpinyl acetate but suggest that it is this component of the essential oil that exhibits cytotoxic activity to UMSCC1 tumor cells [19].

Extracts obtained from the roots of Levisticum officinale W.D.J. Koch demonstrated activity against α-glucosidase, which can be used in the future in the treatment of diabetes, metastatic cancer and lysosomal accumulation disease. At the same time, this extract may have an antiviral effect against HIV and hepatitis [20]. The positive effect of Levisticum officinale W.D.J. Koch extract on the improvement of spatial learning and memory due to the neurotrophic, anti-inflammatory and antioxidant properties of its biologically active components has been experimentally revealed. This effect can be justified by the influence of natural flavonoids, including quercetin, which has a strong antioxidant effect and the ability to capture free radicals when exposed to oxidizing agents [21]. Research by A Khan et al. is being carried out is also confirmed that natural quercetin improves memory characteristics in animals, as a neuroprotector significantly alters synaptic loss in the cortex and hippocampus of the brain of adult mice caused by a powerful neuroinflammatory stimulator - lipopolysaccharide. It should be noted that quercetin can also have antitumor, antiapoptotic, antithrombic effects [22].

In addition to quercetin, chlorogenic acid contained in the rhizomes and roots of Levisticum officinale W.D.J. Koch can have a neuroprotective effect. Its potential neuroprotective effects are determined by suppressing the activity of acetylcholinesterase and inhibition of malondialdehyde in the hippocampus and frontal cortex of the brain [23].

Bioactivity of the tetramethylpyrazine alkaloid contained in the rhizomes of Levisticum officinale W.D.J. Koch is associated with a strong effect on calcium channels (improvement of microcirculation and counteraction to calcium), as well as antiplatelet, anti-inflammatory effects. One of the possible mechanisms of tetramethylpyrazine action on platelet adhesion is shown in a model of vascular endothelial cell damage, where after their damage by oxygen-glucose deprivation/reoxygenation. It is explained by indirect inhibition of the P38 MAPK and NF-KB signaling pathways. As a natural alkaloid, it can have a therapeutic effect in liver fibrosis by stimulating autophagy to reduce inflammation by inhibiting the AKT-mTOR signaling pathway [24]. In an in vitro experimental work on a human-derived SH-SY5Y cell line after sevoflurane treatment, the effect of tetramethylpyrazine was determined, which demonstrated neuroprotective and axon growth-stimulating effects and improved cognitive deficits. The authors believe that the mechanism of attenuation of neurotoxicity is due to increased autophagy via the GPR50/CREB pathway in SH-SY5Y cells. In studies of the effect of tetramethylpyrazine on neurotoxicity in neurons on cells of the SH-SY5Y line caused by the bupivacaine compound, similar results were shown. The mechanism of action of tetramethylpyrazine in this case is explained by inhibition of apoptosis and induction of autophagy in SH-SY5Y cells. Such results allow tetramethypyrazine to be attributed to potential agents for treatment [25].

There is evidence that tetramethylpyrazine relieves diabetic nephropathy, which is one of the most serious complications of diabetes. In an animal experiment with streptozotocin-nicotinamide-induced type 2 diabetes, the administration of tetramethylpyrazine in various doses improved the diabetic condition of rats (an increase in body weight and insulin and a decrease in fasting blood glucose and glycosylated hemoglobin levels). At the same time, a decrease in the level of bladder, serum creatinine, urinary protein and oxidative stress was observed, which indicates an improvement in diabetic nephropathy in rats with type 2 diabetes [26].

Conclusion

The pharmacological effect of plant raw materials Levisticum officinale W.D.J. Koch is due to the presence of biologically active substances of various structures and compositions in plants. Many of them have anti-inflammatory, antibacterial antifungal and antioxidant effects. Levisticum officinale W.D.J. Koch phthalides are also characterized by hepatoprotective properties; flavonoids have cytotoxic effects against tumor cells, neuroprotective and antithrombic effects, in small concentrations they have a positive effect on the reproductive system. The properties of chlorogenic acids Levisticum officinale W.D.J. Koch include antinociceptive and antihypertensive effects. Polyacetylenes are capable of suppressing the growth of tumor cells, bioactive in relation to antiplatelet aggregation. The most significant alkaloid of plant raw materials Levisticum officinale W.D.J. Koch is tetramethylpyrazine, whose bioactivity is due to antiplatelet, anti-inflammatory and neuroprotective effects.

Due to the complex of bioactive compounds and individual components isolated from various parts of Levisticum officinale W.D.J. Koch with a wide spectrum of pharmacological action, the prospect of its use in medical and pharmaceutical practice can be indicated.

Конфликт интересов Не указан.

Conflict of Interest None declared.

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