JP3968179B2 - Treatment for diabetic peripheral nerve injury - Google Patents

Description

【００２７】
【発明の効果】
本発明は、白内障などの糖尿病性末梢神経傷害の発症要因（因子）がアルドース還元酵素（アルドースレダクターゼ）によりブドウ糖などのアルドースが還元されてソルビトールが蓄積されることに鑑み、前記アルドース還元酵素の活性阻害作用を有する新規な天然植物由来の糖尿病性末梢神経傷害治療剤を提供するものである。
【００２８】
本発明の前記治療剤は、今日まで白内障の治療剤として使用されたことがない紅景天属（Ｒｈｏｄｉｏｌａ ｓａｃｒａ）などの紅景天属（Ｒｈｏｄｉｏｌａ、ベンケイソウ科）植物を基源とするものであり、長期間の使用が前提となる糖尿病性末梢神経傷害の治療剤として極めて有用なものである。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a drug effective against diabetic peripheral nerve injury such as cataract based on natural plants (hereinafter also referred to as therapeutic agent for diabetic peripheral nerve injury).
[0002]
More specifically, the present invention relates to a therapeutic agent for diabetic peripheral nerve injury having an activity inhibitory activity of aldose reductase (aldose reductase) containing a red genus plant (Rhodiola) as an active ingredient. Is.
[0003]
[Prior art]
When aldose such as glucose increases in diabetes, the activity of an enzyme (aldose reductase) that reduces the aldose increases.
This type of aldose reductase is found in many places in the body. For example, in an ophthalmic lens, aldose such as glucose is reduced by aldose reductase, resulting in an increase in sorbitol and fructose, thereby causing a problem of promoting cataract progression.
For this reason, the aldose reductase activity inhibitor is known as a therapeutic agent for cataract.
[0004]
Glucose (glycogen) in the body is metabolized mainly in the glycolytic system and is a source of energy. On the other hand, if an abnormality in blood glucose level such as hyperglycemia continues for a long period of time, other metabolic systems that are not glycolytic are activated in an attempt to lower the blood glucose level as much as possible. That is, it is known that there is a pathway in which blood glucose showing a blood glucose level is reduced to sorbitol and further metabolized to fructose, and this metabolic system is called a polyol metabolic system.
[0005]
The above-described enzyme that reduces glucose to sorbitol is called sorbitol reductase. Among them, the polyol metabolic system, particularly the metabolic system for converting sorbitol to fructose is very slow, and sorbitol accumulates in cells. Various problems arise due to sorbitol accumulated in the body in this way.
[0006]
For example, it has been experimentally shown that intracellular sorbitol plays an important role as a causative factor of diabetic nerve injury, and thus suppresses the activity of aldose reductase. However, it has come to be considered as a solution to the major problem of diabetic complications.
[0007]
Looking at the distribution in the body of the the aldose reductase (aldose reductase), end treetops nerve, retina, lens, etc. many kidney, both of which coincides with sites diabetic complications likely to develop.
[0008]
As aldose reductase activity inhibitors, those utilizing components belonging to flavonoids are known in natural products.
However, since there are many unknown fields such as effectiveness in humans, there is a strong demand for more effective drugs, and safe and inexpensive inhibitors of aldose reductase activity.
[0009]
[Problems to be solved by the invention]
The present invention has been devised in view of the limitations of the prior art described above.
The present inventor must treat the side effects seen in conventional synthetic drugs for diabetic complications more than effectiveness, and because of the nature of the disease, diabetic complications, it is a long-term treatment. The development of a therapeutic agent for diabetic peripheral nerve injury was promoted from the standpoint that it would be optimal for the prevention of cancer and onset if it is a food or a natural product that is traditionally known to be effective. .
[0010]
As a result, the present inventor has found that Rhodiola sacra, which has not been used as a therapeutic agent for cataracts until now, significantly inhibits the activity of aldose reductase.
The present invention is based on the above findings, and the present invention provides a therapeutic agent for diabetic peripheral nerve injury that is highly biologically safe and has an excellent activity of inhibiting aldose reductase activity.
[0011]
[Means for solving problems]
In general, the present invention relates to the activity of aldose reductase (aldose reductase) containing as an active ingredient powder and / or extract of a red genus (Rhodiola). The present invention relates to a therapeutic agent for diabetic peripheral nerve injury having an inhibitory action.
[0012]
The technical configuration and embodiments of the present invention will be described in detail below.
[0013]
First, since the present invention relates to a new therapeutic agent based on natural plants as described above, it will be explained from the reason that importance is attached to natural plants instead of conventional chemical substances (synthetic substances).
[0014]
From the viewpoint of preventive medicine as described above, the present inventor has examined the aldose reductase activity inhibition of the ophthalmic lens as an index for a large number of natural products that have been used for food and traditionally used drugs of various ethnic groups. did.
More specifically, aldose reductase was extracted from rat eye lenses, and a number of natural products that were found to have an inhibitory effect on this enzyme reaction were screened to study their effectiveness.
[0015]
In the above-described research process, the present inventor has found that the red ginseng powder or solvent extract has an activity of inhibiting the activity of aldose reductase. Of course, the fact that the red scenic sky has such characteristics is not known at all.
[0016]
Next, the Hongjing genus plant which is an active ingredient of the therapeutic agent for diabetic peripheral nerve injury of the present invention will be described.
In Japan, it is not known that Benjing celestial belonging to the family Benxisaceae is more medicinal, more specifically, Benxis, which is the same companion as the Benxis.
On the other hand, Tibet, Yunnan, Guizhou, etc., mainly in the alpine rocks of China, have been given their crude drug names due to differences in the source plants. According to the Chinese medicinal plant dictionary “Shanghai Science and Technology Publishing” (Shanghai Science and Technology Press), its use is indicated for internal use for hemostasis, antitussive, etc., and for external use for bruises and burns. Has been. In Tibet and the former Soviet Union, it is also known to be used as a tonic in addition to the above purpose.
[0017]
Examples of the Rhodiola plant that is an active ingredient of the therapeutic agent for diabetic peripheral nerve injury of the present invention are as follows. Hereinafter, examples are given in the order of plant names (scientific names / production areas).
Kyokoku Kageten (R.algida / Aomi, Haiboku, Haisai), Karako Benkeiten (R.algida var.Tangutica / Shikawa), Nishikawa Kageten (R.alsia / Sichuan), Koza Beni Kageten (R. dumulosa / Sichuan, Gansu), Ohana Seiten (R. eurphylla / Northwest of Yun, Tibet), Changshu Jingten (R.fastigita / Southwest of Yun, Tibet), Nagasaku Kageten (R .. gelida / Utenyama), R.henryi / Gansu, Henan, Hubei, Sichuan, Guizhou), Ascension's red view (R.heterodonta / Xinjiang, Tibet), Nanaha Kageten (R. Kirirowii / Hebei, Shanxi, Yunnan, Sichuan, Tibet), Shiryu Benkei (R. quadrifida / Gansu, Aomi, Niigata, Sichuan, Tibet), R. Sacharine nsis / Heilongjiang, Jilin), Red Scenic Spots (All Ben) (R. sacra / Northern Southwest of Tibet, Southeast Tibet), ▲ Construction Red Scenery (R.scabrida / Western Sichuan, Northwestern Clouds), coarse Stem red scenic sky (R. wallichiana / northwestern south of Tibet, Southeast Tibet), large stock stem scenic red sky (R. wallichiana var. Cholaensis / Qinghai, northwest south of Yun), Yunnan red scenic sky (R. yunnanensis / northwestern lake) ),
Etc. can be illustrated.
As the production area of the Hong Kong genus plant, Tibet, Sichuan Province, Yunnan Province of the People's Republic of China are famous.
The red scenic heaven used in the present invention is imported from whole Tibet, Sichuan Province, or Yunnan Province, mainly imported from the People's Republic of China. It is.
[0018]
In the therapeutic agent for diabetic peripheral nerve injury according to the present invention, the active ingredient of the red genus plant such as Benjing Tenten is a powdery one or an extract extracted with a desired solvent such as water or alcohol, May be in the form of a mixture thereof.
In addition, in the red celestial plant, for example, the red celestial heaven, all parts can be used, but it is particularly economical and efficient to use the whole grass part.
[0019]
In order to prepare a powder body or an extract from a red scenic plant such as the above red scenic heaven, it may be carried out in a desired manner, but an example thereof is shown below.
For example, the red-viewed celestial powder body may be made into a powder form of about 100 to 150 mesh by an ordinary pulverizer.
Moreover, the solvent extract of Hongkage Ten is added under 3 to 51 solvents (water or alcohol such as methanol or ethanol) to 1 kg of Benjing Tenn Powder and is extracted under heating or cooling. In the case of warming, it is allowed to stand at 80 to 90 ° C. for 3 hours, and in the case of cold temperature, it is allowed to stand at room temperature for 3 days and then filtered. The filtrate is concentrated under reduced pressure at 45 ° C. or lower, and the solvent is completely distilled off to dry extract. And it is sufficient.
In the present invention, an anti-diabetic agent in the form of granules or tablets may be obtained by adding an appropriate excipient or lactose or starch to the powder or extract.
Furthermore, in the present invention, the roughly cut red scenic heaven may be decocted and used as a tea preparation.
In the present invention, the solvent used in the solvent extraction method is water, hydrous alcohol, alcohol or the like. As the alcohol, lower alcohol, particularly ethyl alcohol is preferable from the viewpoint of safety. Moreover, although the density | concentration of the said hydrous alcohol is not specifically limited, What is necessary is just to use a 30-90%, normally 40-70% density | concentration.
[0020]
The dosage of the therapeutic agent for diabetic peripheral nerve injury of the present invention varies depending on the age and symptoms, but the effective amount for adults is usually 2-3 g at a time for red ginseng powder, with water extract or alcohol extract. 800 mg to 1500 mg, preferably taken 3 times at a time.
[0021]
Hereinafter, the present invention will be described in more detail with reference to examples.
Needless to say, the present invention is not limited to the examples.
[0022]
(1). Preparation of the extract of red scenic extract The scenic extract of red scenic is roughly cut into 100-150 mesh powder, and then extracted with water, water-containing alcohol, or a solvent such as alcohol. Can be prepared.
Specifically, an extract was prepared by performing the following extraction operation.
That is, 5 kg of a solvent such as water or alcohol was added to 1 kg of scooped or pulverized red scenic heaven, heated at around 90 ° C., filtered after 3 hours, and the filtrate was concentrated under reduced pressure at 45 ° C. or lower to obtain water extract and alcohol, respectively. I got an extract. The yield of the extract was extremely high, and all were around 45% to 50%.
[0023]
(2). Inhibition test of aldose reductase activity The isolation and reaction of aldose reductase from rat eye lenses was modified slightly by the method of Duflane et al. [Dufrane SP et al, Biochem. Med. 32, 99-105 (1985)]. In addition.
That is, the rat eye lens was homogenized with 135 mM Na containing 10 mM 2-mercaptoethanol and K-phosphate buffer pH 7.0, and then centrifuged at 10 g for 30 minutes, and the supernatant was used as an enzyme solution.
The reaction was performed as follows. That is, 100 mM LiSO ₄ , 0.03 mM NADPH, 1 mM D6-glyceraldehyde was added to 135 mM Na, K-phosphate buffer pH 7.0, and 100 μl of enzyme solution was added. The total volume was 0.5 ml and the added sample was 25 μl, and the sample was dissolved in DMSO. Then, NADPH was added, 30 ° C. for 30 minutes, and 150 μl of 0.5N HCl was added to stop the reaction.
[0024]
Measurement of aldose reductase activity inhibition was performed as follows.
In other words, 0.5 ml of 6N NaOH containing 10 mM imidazole was added, heated at 60 ° C. for 10 minutes, and the amount of NADP produced by changing NADPH was measured with a fluorometer.
[0025]
The results are shown in Table 1 below.
As is clear from Table 1, the activity inhibition of aldose reductase was observed in any of the water and alcohol extract of Ohana Kagekeiten, Sekiji Kagekeiten, Zenben Benkeikeiten and Shiveru Kagekeiten. It was. In addition, epalrestat (manufactured by Ono Pharmaceutical Co., Ltd.) was used as a comparative control drug.
[0026]
[Table 1]

[0027]
【The invention's effect】
In view of the fact that the onset factor (factor) of diabetic peripheral nerve injury such as cataract is reduced by aldose reductase (aldose reductase) and aldose such as glucose is reduced and sorbitol is accumulated, the activity of the aldose reductase The present invention provides a novel natural plant-derived diabetic peripheral nerve injury therapeutic agent having an inhibitory action.
[0028]
The therapeutic agent of the present invention is based on a plant of the red genus (Rhodiola), which has not been used as a therapeutic agent for cataracts until now. It is extremely useful as a therapeutic agent for diabetic peripheral nerve injury which is premised on long-term use.

Claims (1)

In a therapeutic agent for diabetic peripheral nerve injury comprising a powder and / or extract of a red violet (Rhodiala) plant as an active ingredient, the red celestial genus plant comprises: A therapeutic agent for diabetic peripheral nerve injury, wherein the therapeutic agent is at least one selected from the group consisting of Zenben Benkeiten and Shien Benkeiten .