JP2006241051A - Anti-stress agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an anti-stress agent exhibiting high anti-stress effects. <P>SOLUTION: The anti-stress agent comprises at least one kind selected from limonene, a metabolite of the limonene, terpinene and citral as an active ingredient and has anti-stress actions. Furthermore, the anti-stress actions are actions for relaxing a stress state induced during laying of physical stress and mental stress. The anti-stress agent comprising an essential oil of citrus fruits as the active ingredient can be provided. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an anti-stress agent having an anti-stress action.

As this type of anti-stress agent, those containing animal and plant extracts as disclosed in Patent Documents 1 to 10 are known.
JP 2001-335505 A JP 2002-080363 A Japanese Patent Laid-Open No. 2001-354583 JP 2001-226281 A JP 2001-213792 A JP 2000-351710 A JP 2000-229876 A JP 2000-143521 A JP 2000-103740 A JP 2000-136143 A

  According to the present invention, when limonene, terpinene, and citral were each administered into the living body of an experimental animal, the secretion of hormones as an indicator of the stress state was suppressed, and the stress state of the experimental animal was It was made as a result of confirming that it was relaxed. The purpose is to provide an anti-stress agent capable of exhibiting a high anti-stress effect.

  In order to achieve the above object, the anti-stress agent according to claim 1 has an anti-stress action, comprising at least one selected from limonene, a metabolite of limonene, terpinene and citral as an active ingredient. To do.

The gist of the anti-stress agent according to claim 2 is that it contains citrus essential oil as an active ingredient and has an anti-stress action.
The anti-stress agent according to claim 3 is the invention according to claim 1 or claim 2, wherein the anti-stress action is an action to relieve a stress state induced at the time of physical stress load and psychological stress load. It is a summary.

  ADVANTAGE OF THE INVENTION According to this invention, the antistress agent which can exhibit a high antistress effect can be provided.

Hereinafter, an embodiment in which the present invention is embodied in an anti-stress agent will be described.
The antistress agent of this embodiment contains at least one selected from limonene, terpinene, and citral as an active ingredient. This anti-stress agent, when administered in vivo, reduces the secretion of hormones as an indicator of the stress state by the action of the active ingredient, and exerts an effect of relaxing the stress state of the living body, that is, an anti-stress effect can do. This anti-stress agent can exert an anti-stress effect against both physical stress and psychological stress (mental stress). Examples of the hormone include corticosterone that is secreted in the animal body when subjected to physical stress and / or psychological stress and has been reported to show an individual's stress state. . Corticosterone is a hormone that is synthesized primarily in the bundled layer of the adrenal cortex.

  Limonene and terpinene are both classified as monoterpene hydrocarbons and are the main components of essential oils (essential oils) of citrus fruits such as lemon, grapefruit and orange. These monoterpene hydrocarbons are known to have antistagnation, anti-inflammatory and antiviral effects, as well as antibacterial and steroid hormone-like effects. There are two types of limonene: R-limonene (D-limonene) and S-limonene (L-limonene), which are optical isomers that are mirror images of each other. R-limonene is highly contained in essential oils of citrus fruits such as lemon, and S-limonene is contained in essential oils of berries such as raspberries. Known physiological activities unique to limonene include liver tonicity, kidney function promotion, and peristaltic movement promotion. Among terpinenes, γ-terpinene is known to have specific physiological activities such as venous tonicity and stagnation-removing action.

  Citral is classified as a terpene aldehyde and is highly contained in citrus essential oils such as lemon and lemongrass. Terpene-based aldehydes containing citral are known for their anti-inflammatory and antifungal effects, as well as analgesic, litholytic, sedative, digestive, antihypertensive, antiviral, and antibacterial effects Yes. As the physiological activity inherent to citral, antihistamine action, antibacterial action, antifungal action, sedative action and the like are known.

  This anti-stress agent is preferably taken orally in the form of food or drink. In addition, this anti-stress agent may be administered in vivo by a method of continuous administration (such as aromatherapy) through the olfactory organ, a method of absorption from the skin, or injection, etc. In this case, it is exactly the same as in the case of oral administration. The effect of can be demonstrated. That is, this anti-stress agent can be used as a pharmaceutical, a quasi-drug, a cosmetic, or a food or drink (health food). In addition, the anti-stress agent can be used as a perfume such as perfume, incense, soaps, candles, indoor air fresheners, or sundries. In order to exert the antistress action most simply and effectively, it is desirable that these antistress agents are absorbed into the body by ingestion. By absorbing in this way, the effect is easily sustained.

  Therefore, since the anti-stress agent of this embodiment contains at least one selected from limonene, terpinene, and citral as an active ingredient, it exerts an effect of alleviating the stress state of the living body when administered in vivo. . For this reason, this anti-stress agent can exhibit a high anti-stress effect through reduction of physical and psychological stress. In the modern society, various mental and physical stresses from childhood to old age continuously exert a burden on the body and mind, which is a big social problem. In particular, it has been pointed out that chronic stress is associated with mental disorders such as depression and anxiety. The anti-stress agent of this embodiment is particularly useful for eliminating such a chronic stress state.

<Communication box experiment>
In psychosomatic medicine, it is known that there is a deep connection between behavioral and emotional changes and changes in stomach morphology and function. By applying stress to an animal, it is possible to induce a stress ulcer in the gastric mucosa of the animal and create a stress (ulcer) model. By examining the model, an antiulcer drug, an anxiolytic drug, Efficacy evaluation such as antidepressant can be performed. Stress ulcers in humans are mainly caused by psychological and mental stress. For this reason, a physical stress model can be created and tested by applying physical stress such as the water immersion method, restraint method, and floor electric shock method (foot stimulation by electric shock from the floor grid). Although important, it is particularly important to create a psychological stress model and test it.

  Such a psychological stress model can be created and tested by a communication box experiment. The communication box experiment was performed according to the method of Hayashi et al. (Pharmaceutical Journal 121 (10) 753-759 (2001)). That is, the emotional response of an animal (hereinafter referred to as “animal A” or “rat A”) loaded with physical stress (in this example, stress by floor electric shock method) is transferred to another animal that is not loaded with physical stress ( Hereinafter, the purpose is to load the animal B with psychological stress by observing the animal B or rat B). This makes it possible to create a stress model that is very close to a stress ulcer in humans.

  Specifically, 6 Wistar clean rats (manufactured by Japan SLC Co., Ltd.) 5 weeks old (body weight of about 100 g) were prepared for each group. These rats were preliminarily raised for 3 days with a commercial feed (CE-2; manufactured by CLEA Japan) and tap water. Each box of rats after preliminary breeding was subjected to a communication box experiment applying the floor electric shock method.

  That is, rat A in the section with electric shock is given electrical stimulation from the electric wire on the floor. In this electrical stimulation, a current of 5 mA is conducted to the electric wire for 5 seconds, and then an electric current of 5 mA is again conducted to the electric wire for 5 seconds at intervals of 25 seconds. For this reason, the rat A in the section with electrical shock directly receives pain (physical stress) due to electrical stimulation, and therefore screams and jumps out while excreting urine during electrical stimulation. On the other hand, the rat B in the non-electric shock section is housed in a box adjacent to the box containing the rat A in the lightning section and a transparent panel. For this reason, although rat B does not receive electrical stimulation directly, it has a strong psychological anxiety (psychology) due to the scream, stool odor, and jumping of rat A in the adjacent box and also in the surrounding boxes. Stress). As a result, the rat B in the non-electric shock category becomes an experimental system (stress model) for purely evaluating psychological and emotional stress.

  As a control group, two groups consisting of rats in which 100 μL of physiological saline was administered intraperitoneally per 100 g of body weight were prepared. One control group was a rat A with electric shock, and the other control group was a rat with no electric shock. B. As test groups, instead of the physiological saline, two groups each consisting of rats administered intraperitoneally with 100 μL of R-limonene, 100 μL of S-limonene or 100 μL of γ-terpinene (all manufactured by Sigma) were prepared, One control group was Rat A in the section with electrical shock, and the other control group was Rat B in the section without electrical shock, and the test was performed in the same manner as in the control group. In addition, as another control group, one group was prepared, which consisted of rats intraperitoneally administered with 100 μL of physiological saline per 100 g of body weight and was not loaded with either physical stress or psychological stress.

  After collecting blood from each group of rats after completion of the communication box experiment, serum corticosterone concentration was measured using HPLC. The average value and standard deviation of serum corticosterone concentration in each group are shown in Table 1 below. In addition, when stress (physical stress or psychological stress) is applied to rats, it is known that serum corticosterone concentration increases.

表１より、対照群のラットでは、肉体的ストレス及び心理的ストレスのいずれのストレスを負荷した場合でも、血清中コルチコステロン濃度の大幅な上昇が確認された。各試験群の電撃あり区分のラットＡでは、対照群の電撃あり区分のラットＡと比較して、いずれも血清中コルチコステロン濃度が半分未満に抑えられていた。また、電撃あり区分のラットＡにおいては、Ｓ−リモネン投与群及びγ−テルピネン投与群における血清中コルチコステロン濃度は、Ｒ−リモネン投与群よりも若干ではあるが低下していたことも確認された。

From Table 1, in the rats of the control group, a significant increase in the serum corticosterone concentration was confirmed when either physical stress or psychological stress was applied. Rat A in each test group with electric shock had a serum corticosterone concentration less than half that of rat A in the electric shock group in the control group. It was also confirmed that in rat A with electric shock, the serum corticosterone concentration in the S-limonene-administered group and γ-terpinene-administered group was slightly lower than that in the R-limonene-administered group. It was.

  On the other hand, in each test group, rat B in the non-lightning group, the serum corticosterone concentration was suppressed to about half as compared with rat B in the non-lightning group of the control group. In addition, suppression of increase in serum corticosterone concentration was confirmed in the order of the S-limonene administration group, the γ-terpinene administration group, and the R-limonene administration group. S-limonene-administered group showed a stronger tendency to suppress the increase in serum corticosterone concentration than R-limonene-administered group even in the non-electric shock category, and there was a difference in stress-reducing effect depending on optical isomers even in the same limonene Was recognized.

<Cold stress experiment>
Six 10-week-old Wistar clean rats (manufactured by Japan SLC) were prepared for each group. These rats were preliminarily raised for 2 weeks in a commercial feed (CE-2; manufactured by Claire Japan) and tap water. A cold stress experiment was performed on each group of rats after preliminary breeding.

  That is, as a control group, two groups consisting of rats in which 100 μL of physiological saline was administered intraperitoneally per 100 g of body weight were prepared, and the rats of one control group were bred at normal breeding temperature (26 ° C.) for 2 hours. The rats of the other control group were subjected to cold stress by raising them in a refrigerator at 4 ° C. for 2 hours. As test groups, instead of the physiological saline, R-limonene 100 μL, S-limonene 100 μL, γ-terpinene 100 μL or citral 100 μL (all manufactured by Sigma) were administered at a temperature of 4 ° C. Reared for 2 hours.

  After collecting blood from each group of rats after the end of the cold stress experiment, serum corticosterone concentration was measured using HPLC. The average values and standard deviations of serum corticosterone concentrations in each group are shown in Table 2 below. In this cold stress test, the effects of physical and psychological stress on rats can be examined.

表２より、対照群のラットでは、寒冷ストレスを負荷した場合、血清中コルチコステロン濃度の上昇が確認された。寒冷ストレスを負荷したラットでは、Ｒ−リモネン、Ｓ−リモネン、γ−テルピネン及びシトラールのいずれを投与した場合でも、血清中コルチコステロン濃度の上昇が有意に抑えられていた。特に、Ｓ−リモネン投与群で、血清中コルチコステロン濃度の上昇を抑える効果が高かった。

From Table 2, in the rats of the control group, an increase in serum corticosterone concentration was confirmed when cold stress was applied. In rats loaded with cold stress, an increase in serum corticosterone concentration was significantly suppressed when any of R-limonene, S-limonene, γ-terpinene and citral was administered. In particular, in the S-limonene administration group, the effect of suppressing an increase in serum corticosterone concentration was high.

In addition, this embodiment can also be changed and embodied as follows.
-It is also possible to provide an anti-stress agent containing citrus essential oil as an active ingredient. Since the citrus essential oil contains a large amount of limonene, terpinene, and citral, a high anti-stress effect can be exerted by in vivo administration as in the above embodiment.

  -Limonene metabolites may be used as active ingredients of antistress agents. When limonene is metabolized in vivo, it produces perilla alcohol via perillic acid. That is, examples of the metabolite of limonene include perillic acid and perilla alcohol, and also perylaldehyde. There are two types of perillic acid (perillic acid or perilla acid): R-perillic acid and S-perillic acid, which are optical isomers that are mirror images of each other. As perilla alcohol (perillyl alcohol), there are two types of optical isomers, R-perilla alcohol and S-perilla alcohol, which are mirror images of each other.

  In this case, a high anti-stress effect can be exhibited in the same manner as when an anti-stress agent containing limonene as an active ingredient is administered in vivo. Furthermore, the antistress agent containing a limonene metabolite can further eliminate the process of converting the limonene into a limonene metabolite in vivo when an antistress agent containing limonene is administered. A quick anti-stress effect can be exhibited.

Further, the technical idea that can be grasped from the embodiment will be described below.
The antistress agent according to any one of claims 1 to 3, wherein the active ingredient is S-limonene.

  The antistress action is an action to alleviate a stress state induced at the time of stress load related to an increase in serum corticosterone concentration. The antistress agent described.

Claims (3)

  An anti-stress agent characterized by having at least one selected from limonene, a limonene metabolite, terpinene and citral as an active ingredient and having an anti-stress action.   An anti-stress agent characterized by having citrus essential oil as an active ingredient and having an anti-stress effect.   The anti-stress agent according to claim 1 or 2, wherein the anti-stress action is an action to relieve a stress state induced at the time of physical stress load and psychological stress load.