KR100717872B1 - A therapeutic agent for treating estrogen deficiency syndrome - Google Patents

Abstract

The present invention relates to a new pharmaceutical use of ginsenoside Rb1, and more particularly, to a drug for treating estrogen deficiency syndrome comprising ginsenoside Rb1 or a pharmaceutically acceptable salt as an active ingredient. It is about.

Ginsenoside Rb1, Estrogen

Description

A therapeutic agent for treating estrogen deficiency syndrome

1 is a graph showing the effect of ginsenoside Rb1 on the activity of luciferase induced by estrogen,

2 is a graph showing the effect of ginsenonoside Rb1 on the activity of luciferase induced by retinoic acid,

3 is a graph showing the effect of ginsenoside Rb1 on the activity of androgen-induced luciferase,

4 is a graph showing the effect of ginsenoside Rb1 on the activity of luciferase induced by glucocorticoids.

The present invention relates to a new medicinal use of ginsenoside Rb1, and more particularly, to a drug for treating estrogen deficiency syndrome comprising ginsenoside Rb1 or a pharmaceutically acceptable salt as an active ingredient. It is about.                         

Estrogen, also known as female hormone, is one of the steroid hormones. Its reproductive function and physiological control are mediated through estrogen receptors distributed in various tissues such as the reproductive system such as uterus and breast, central nervous system, cardiovascular system, immune system, digestive system, kidney and lung It is known to perform a function. Estrogens function by producing ovaries, reaching the target cells through blood vessels, entering the target cells by simple diffusion, and affecting the transcriptional activity of the target genes through the estrogen receptor, a transcription factor present in the nucleus.

Estrogen receptor (ER) is one of steroid hormone receptors such as glucocorticoid receptor (GR), progesterone receptor (PR), androgen receptor (AR), mineralocorticoid receptor (MR), and estradiol, cortisol, progesterone , Testosterone, aldosterone and the like are known to act as relative ligands of these receptors (Barrett TJ et al., 1999: Vitam Horm. 55, 127-163).

The main physiological effects of estrogens are endometrial proliferation, uterine muscle development, secondary sexual manifestations, mediation of menstrual cycle, maternal change during pregnancy, and mammary gland proliferation secretion. It is clinically used for treatment of amenorrhea or dysmenorrhea, artificial movement of menstruation, menopausal syndrome including osteoporosis, hyperlipidemia, obesity and hypertension, and hormone therapy for prostate cancer or breast cancer.

In particular, menopause syndrome, including osteoporosis that occurs before and after menopause, is due to a decrease in estrogen secretion, which is due to a decrease in the number of eggs in both ovaries and a decrease in ovarian function, leading to a significant decrease in estrogen secretion. . Since estrogen is involved in the secretion of vasodilatation prostaglandins and nitric oxide (NO), a decrease in estrogen secretion affects capillaries, causing irregular vasodilation and causing typical symptoms such as a burning face. do. In addition, since estrogen has a function of protecting the heart and maintaining an appropriate blood pressure, and has a function of inhibiting arteriosclerosis of the coronary arteries, hypertension may occur in menopause when estrogen secretion is reduced.

Postmenopausal osteoporosis due to lack of estrogen secretion, and decrease in estrogen secretion decreases 8% of the high-density lipoprotein (HDL) -bound cholesterol, while 10% of the low-density lipoprotein (LDL) -binding cholesterol is harmful. Increases. Good cholesterol helps clean up the lining of your blood vessels, while bad cholesterol causes debris to accumulate. Therefore, during menopause, the level of triglycerides, a form of fat storage, increases, and the risk of developing hyperlipidemia, insulin resistance and obesity also increases.

The conventional method for treating the above-mentioned imbalance of estrogen secretion, namely estrogen deficiency syndrome, has to rely on hormone therapy in which the hormone is directly administered to the body. However, these hormonal therapies have been reported to have serious side effects such as increased frequency of endometrial and breast cancer, increased cholecystitis and gallstones, uterine pain, migraine, swelling, depression, vomiting and nausea.

In recent years, attempts have been made to achieve the same effects as the administration of estrogens while reducing side effects due to the administration of estrogens by using estrogen-like substances, namely, phytoestrogens, through natural foods and beauty foods. Phytoestrogens refer to estrogen-like substances present in plants. These phytoestrogens refer to substances that bind to estrogen receptors in the body and then act as estrogens or antiestrogens depending on tissues. For example, plant-derived compounds such as Genistein and Dizadine (Setchell KD et al., 1987: J. Chromatogr. 386, 315-323) are known to exhibit estrogen-like activity (Tham DM et al., 1998; J. Clin. Endocrinol. Metab. 83, 2223-2353). Soybeans are also known to be rich in phytoestrogens.

Therefore, the present inventors have conducted research to develop a new therapeutic agent that can treat the imbalance of estrogen secretion, that is, estrogen deficiency syndrome, indicating that ginsenoside Rb1, one of ginseng saponins, exhibits estrogen activity by selectively binding to the estrogen receptor. Discovered to complete the present invention.

Accordingly, an object of the present invention is to provide an agent for treating estrogen deficiency syndrome, including menopausal syndrome, comprising ginsenoside Rb1 or a pharmaceutically acceptable salt as an active ingredient.

In order to achieve the above object, the present invention,

Provided is a drug for treating estrogen deficiency syndrome comprising ginsenoside Rb1 or a pharmaceutically acceptable salt as an active ingredient.

Another aspect of the present invention provides a therapeutic agent for menopausal syndrome comprising ginsenoside Rb1 or a pharmaceutically acceptable salt as an active ingredient.

Hereinafter, the present invention will be described in more detail.

Ginsenoside Rb1, which is one of ginseng saponins contained as an active ingredient in the therapeutic agent according to the present invention, has a structure having the structure of Formula 1 below, and has four trans-ring structures.

In the above formula, glc is glucose and ginsenoside Rb1 can be purchased commercially (Wako Co., Japan).

Ginsenoside Rb1 of the present invention can be used as such or in the form of a pharmaceutically acceptable salt. Salts usable in the present invention are not particularly limited as long as they are pharmaceutically acceptable non-toxic salts, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid. Acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and the like.

The term "estrogen deficiency syndrome" used in the present invention is a general term for all symptoms due to estrogen deficiency, and refers to a disease or condition such as menopause syndrome, amenorrhea or dysmenorrhea.

In particular, as can be seen in the following examples, ginsenoside Rb1 binds to the estrogen receptor and exhibits estrogen-like activity, whereas other steroid receptors, namely androgen receptors, glucocorticoid receptors and retinoic acid receptors, are affected. Because it has no effect, it selectively shows estrogen deficiency syndrome treatment effect. Therefore, the therapeutic agent of the present invention can be used as a therapeutic agent for selective estrogen deficiency syndrome, and side effects due to the action of other steroid receptors, namely breast cancer and uterine cancer, can be avoided.

The therapeutic agent of the present invention can be formulated into various pharmaceutical formulations containing ginsenoside Rb1 as an active ingredient, for example oral or parenteral formulations such as granules, tablets, capsules, injections and the like. When formulating a therapeutic agent of the present invention, various carriers used in medicine, such as excipients or other additives such as stabilizers, emollients, emulsifiers and the like, may be used, if necessary, so long as they do not adversely affect the effect of the active ingredient. In pharmaceutical formulations, the unit content of ginsenoside Rb1 can vary widely depending on the formulation and can be used in accordance with conventional methods.                     

In addition, the therapeutic agent for the estrogen deficiency syndrome of the present invention can be administered in various ways depending on the condition of the patient, for example, the dosage of ginsenoside Rb1 per day in adults It can be 100-300 mg / kg.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited thereto.

Example

In the following examples, the presence of estrogen hormones causes the estrogen receptor to initiate transcriptional activation by binding to the estrogen response element (ERE) in the target gene (Klein-Hitpass L. et al., 1986: Cell 46, 1053-1061), it was tested whether ginsenoside Rb1 can lead to transcriptional activation of the reporter plasmid with ERE.

As estrogen receptor-containing cells, MCF-7 cells (Korea Cell Line Bank KCLB: 30022), which are human breast cancer cells capable of expressing estrogen receptor alpha as well as estrogen receptor beta, were used as target cells.

In addition, luciferase plasmid induced by retinoic acid receptor and retinoic acid (Example 2), and luciferase plasmid induced by androgen receptor and androgen in CV1 cells (Korea Cell Line Bank KCLB: 10070) (Example 3) , And a glucocorticoid receptor and a glucocorticoid-induced luciferase plasmid (Example 4), respectively, were introduced to test whether ginsenoside Rb1 exhibited similar activity to retinoic acid, androgen, and glucocorticoid.

When testing whether ginsenoside Rb1 has glucocorticoid, androgen, estrogen, and retinoid activity, which are ligands of the glucocorticoid receptor, the androgen receptor, the estrogen receptor, and the retinoic acid receptor, respectively, dexamethasone, testosterone, and 17β-estradiol as positive controls. All-trans retinoic acid was used.

Example 1 Estrogen-like Substance Activity in MCF-7 Cells of Ginsenoside Rb1

ERE-tk81-luc (Gehm et al., 1997: Proc. Natl. Acad), a luciferase plasmid (reporter plasmid) with corresponding steroid receptors and hormone response elements in MCF-7 cells 94, 14138-14143), transient transfection, 3 g of ginsenoside Rb1 dissolved in 80% ethanol, left for 48 hours, and then receptor gene assay ). Estradiol was used as a positive control, and the anti-estrogens (ICI 182,780, ICI, Inc.) was also treated with the receptor gene to confirm competition with estradiol.

As can be seen in Figure 1, it can be seen that ginsenoside Rb1 effectively activated the transcription of the estrogen reactive luciferase gene. (In Fig. 1, E2 represents estradiol, E2 + ICI represents estradiol and ICI 182,780, Rb1 represents ginsenoside Rb1, Rb1 + ICI represents ginsenosides Rb1 and ICI 182,780, respectively.)

Example 2 Retinoic Acid-like Material Activity of Ginsenoside Rb1

1 gM all-trans retinoic acid was used as a positive control and CV1 cells instead of MCF-7 cells were used to test whether ginsenoside Rb1 had retinoid activity in the same manner as in Example 1.

As can be seen in Figure 2, ginsenoside Rb1 has no effect on the retinoic acid receptors, it can be seen that it does not have retinoic acid activity (in Figure 2, ATR is trans-retinoic acid, Rb1 is true The results of treatment of the senoside Rb1 are shown.)

Example 3. Androgen-like substance activity of ginsenoside Rb1

Using 100 nM testosterone as a positive control and CV1 cells instead of MCF-7 cells, the ginsenoside Rb1 was tested for androgen activity in the same manner as in Example 1.

As can be seen in Figure 3, ginsenoside Rb1 has no effect on the androgen receptor, it can be seen that it does not have androgen activity. (In Fig. 3, Tes represents testosterone and Rb1 represents the result of treating ginsenoside Rb1, respectively.)

Example 4 Corticosteroid-like Substance Activity of Ginsenoside Rb1

10 g of dexamethasone was used as a positive control and CV1 cells were used instead of MCF-7 cells to test whether ginsenoside Rb1 has androgen activity in the same manner as in Example 1.

As can be seen in Figure 4, ginsenoside Rb1 has no effect on the glucocorticoid receptor, it can be seen that does not have glucocorticoid activity. (In Fig. 4, Dex represents testosterone and Rb1 represents the result of treating ginsenoside Rb1, respectively.)

As can be seen in the above examples, it can be seen that ginsenoside Rb1 selectively exhibits estrogen-like activity without exhibiting activity as a male hormone in the body.

When the therapeutic agent comprising ginsenoside Rb1 according to the present invention is used for alleviation of symptoms caused by estrogen deficiency syndrome including menopausal syndrome, side effects of conventional hormone therapy may be avoided, and in particular, selective estrogen deficiency syndrome may be avoided. It can be cured.

Claims (2)

A therapeutic agent for estrogen deficiency syndrome comprising ginsenoside Rb1 or a pharmaceutically acceptable salt thereof as an active ingredient. The agent according to claim 1, for treating menopause syndrome.

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