JP2013035772A - Leukocyte activation inhibitor - Google Patents
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- JP2013035772A JP2013035772A JP2011172116A JP2011172116A JP2013035772A JP 2013035772 A JP2013035772 A JP 2013035772A JP 2011172116 A JP2011172116 A JP 2011172116A JP 2011172116 A JP2011172116 A JP 2011172116A JP 2013035772 A JP2013035772 A JP 2013035772A
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Abstract
Description
本発明は、Ｓ―アリルグルタチオン及び／又はその塩を含有する白血球活性化抑制剤に関する。 The present invention relates to a leukocyte activation inhibitor containing S-allylglutathione and / or a salt thereof.
炎症とは、生体の免疫応答の結果生じる病理学上の変化をいい、炎症が進行した場合には様々な疾患の原因となる。これまで、多くの炎症抑制効果を有する薬剤が開発されてきた（例えば、特許文献１〜４参照）。これらは白血球の活性抑制により炎症を抑制するものである。 Inflammation refers to pathological changes that occur as a result of the body's immune response. When inflammation progresses, it causes various diseases. Until now, many medicines having an anti-inflammatory effect have been developed (see, for example, Patent Documents 1 to 4). These suppress inflammation by inhibiting leukocyte activity.
また、グルタチオン等の低分子ペプチドには様々な薬理効果があることが知られている。例えば、ペプチドであるカルシウム受容体活性化剤を含有する下痢の予防又は治療剤（特許文献５参照）や、消化管の重炭酸分泌促進剤（特許文献６参照）等である。 In addition, it is known that low molecular weight peptides such as glutathione have various pharmacological effects. For example, a preventive or therapeutic agent for diarrhea containing a calcium receptor activator which is a peptide (see Patent Document 5), a gastrointestinal bicarbonate secretion promoter (see Patent Document 6), and the like.
これまでの炎症抑制剤又は白血球活性化抑制剤は、安全性や有効性の面で十分ではなかった。特に、慢性炎症に対して効果的な炎症抑制剤又は白血球抑制活性化剤が求められていた。 Conventional inflammation inhibitors or leukocyte activation inhibitors have not been sufficient in terms of safety and effectiveness. In particular, there has been a demand for an inflammation inhibitor or leukocyte inhibitory activator effective for chronic inflammation.
本発明は、Ｓ―アリルグルタチオン、Ｓ―アリルグルタチオン誘導体、及びそれらの塩からなる群から選ばれる一又は複数を含有する白血球活性化抑制剤である。 The present invention is a leukocyte activation inhibitor containing one or more selected from the group consisting of S-allylglutathione, S-allylglutathione derivatives, and salts thereof.
また、本発明の白血球活性化抑制剤は、炎症性サイトカインの産出を抑制するものであってもよく、炎症反応を抑制するものであってもよい。 Moreover, the leukocyte activation inhibitor of the present invention may suppress the production of inflammatory cytokines or may suppress the inflammatory reaction.
本発明は、Ｓ―アリルグルタチオン、Ｓ―アリルグルタチオン誘導体、及びそれらの塩からなる群から選ばれる一又は複数を含有することで、白血球の活性化や炎症性サイトカインの産出を抑制し、炎症反応、特に慢性炎症の抑制に効果がある。また、炎症を原因とする様々な疾患の抑制にも用いることができる。 The present invention includes one or more selected from the group consisting of S-allylglutathione, S-allylglutathione derivatives, and salts thereof, thereby suppressing activation of leukocytes and production of inflammatory cytokines, and inflammation reaction , Especially effective in suppressing chronic inflammation. It can also be used to suppress various diseases caused by inflammation.
本発明は、Ｓ―アリルグルタチオン、Ｓ―アリルグルタチオン誘導体、及びそれらの塩からなる群から選ばれる一又は複数を含有する白血球活性化抑制剤である。また、Ｓ―アリルグルタチオン、Ｓ―アリルグルタチオン誘導体、及びそれらの塩からなる群から選ばれる一又は複数を含有する炎症性サイトカイン産出抑制剤、並びにＳ―アリルグルタチオン、Ｓ―アリルグルタチオン誘導体、及びそれらの塩からなる群から選ばれる一又は複数を含有する炎症抑制剤を含む。 The present invention is a leukocyte activation inhibitor containing one or more selected from the group consisting of S-allylglutathione, S-allylglutathione derivatives, and salts thereof. In addition, an inflammatory cytokine production inhibitor containing one or more selected from the group consisting of S-allylglutathione, S-allylglutathione derivatives, and salts thereof, and S-allylglutathione, S-allylglutathione derivatives, and the like An inflammation inhibitor containing one or more selected from the group consisting of the salts of
発明者らはＳ―アリルグルタチオン、Ｓ―アリルグルタチオン誘導体、及びそれらの塩からなる群から選ばれる一又は複数が、活性化した白血球に作用して該白血球からの炎症性サイトカインの産出を抑制すること、さらに炎症を抑制することにより、炎症を原因とする疾患の治療効果を有することを見出し、本発明に到達した。 The inventors suppress the production of inflammatory cytokines from one or more selected from the group consisting of S-allylglutathione, S-allylglutathione derivatives, and salts thereof by acting on activated leukocytes In addition, the present inventors have found that it has a therapeutic effect on diseases caused by inflammation by further suppressing inflammation, and reached the present invention.
Ｓ―アリルグルタチオンとは、Ｓ―アリル化されたγ―Ｌ―グルタミル―Ｌ―システイニルグリシンをいい、化１に示す構造を有する。本発明においては、天然物から単離されたＳ―アリルグルタチオンや、化学的に合成されたＳ―アリルグルタチオン等を用いることができる。 S-allylglutathione is S-allylated γ-L-glutamyl-L-cysteinylglycine, which has the structure shown in Chemical Formula 1. In the present invention, S-allyl glutathione isolated from natural products, chemically synthesized S-allyl glutathione, and the like can be used.
炎症とは、生体の免疫応答の結果生じる病理学上の変化をいう。炎症が進行すると、白血球等の免疫細胞が活性化して浸潤することによってさまざまな障害が起こる。炎症は、進行の経過に従って急性炎症と慢性炎症とに分類されるが、本発明には特に慢性炎症の抑制に効果がある。 Inflammation refers to a pathological change resulting from the immune response of a living body. As inflammation progresses, various disorders occur due to activation and infiltration of immune cells such as leukocytes. Inflammation is classified into acute inflammation and chronic inflammation according to the progress of progression, and the present invention is particularly effective in suppressing chronic inflammation.
白血球は、好中球、好酸球、好塩基球、リンパ球、単球等に分類される。白血球の多くは炎症反応に関わる。例えば、単球が分化してなるマクロファージは、活性化したリンパ球から産出されるサイトカインにより刺激を受け、さらにリンパ球を活性化することで炎症反応が促進される。 Leukocytes are classified into neutrophils, eosinophils, basophils, lymphocytes, monocytes and the like. Many white blood cells are involved in the inflammatory response. For example, macrophages obtained by differentiating monocytes are stimulated by cytokines produced from activated lymphocytes, and the inflammatory reaction is promoted by further activating lymphocytes.
サイトカインは白血球等の免疫細胞から分泌されるタンパク質であり、炎症反応を制御する。なかでも、炎症症状を引き起こすサイトカインを炎症性サイトカインという。炎症性サイトカインは、具体的には、インターロイキン（IL）やインターフェロン（IFN）、腫瘍壊死因子（TNF）等の中で免疫細胞の活性化に関わっているものをいい、例えば、TNFα、TNFβ、IFNγ、IL-1、IL-4、IL-6、IL-8、IL-12等が挙げられる。 Cytokines are proteins secreted from immune cells such as leukocytes and control inflammatory responses. Among these, cytokines that cause inflammatory symptoms are called inflammatory cytokines. Inflammatory cytokines specifically refer to those involved in immune cell activation such as interleukin (IL), interferon (IFN), tumor necrosis factor (TNF), such as TNFα, TNFβ, Examples include IFNγ, IL-1, IL-4, IL-6, IL-8, and IL-12.
本発明に用いられるＳ―アリルグルタチオン、Ｓ―アリルグルタチオン誘導体、及びそれらの塩からなる群から選ばれる一又は複数は、炎症、特に慢性炎症を原因とする疾患の治療及び／又は予防に用いることができる。具体的には動脈硬化、腫瘍、リウマチ、アトピー性皮膚炎等の治療及び／又は予防が挙げられる。したがって、本発明は、Ｓ―アリルグルタチオン、Ｓ―アリルグルタチオン誘導体、及びそれらの塩からなる群から選ばれる一又は複数を含有する動脈硬化の治療及び／又は予防剤、腫瘍の治療及び／又は予防剤、リウマチの治療及び／又は予防剤、アトピー性皮膚炎の治療及び／又は治療剤を提供する。 One or a plurality selected from the group consisting of S-allylglutathione, S-allylglutathione derivatives, and salts thereof used in the present invention is used for treatment and / or prevention of diseases caused by inflammation, particularly chronic inflammation. Can do. Specifically, treatment and / or prevention of arteriosclerosis, tumor, rheumatism, atopic dermatitis and the like can be mentioned. Accordingly, the present invention relates to a therapeutic and / or prophylactic agent for arteriosclerosis, which comprises one or more selected from the group consisting of S-allylglutathione, S-allylglutathione derivatives, and salts thereof, and treatment and / or prevention of tumors. An agent, a therapeutic and / or preventive agent for rheumatism, and a therapeutic and / or therapeutic agent for atopic dermatitis are provided.
さらに、実施例を用いて本発明を詳細に説明するが、本発明は以下の実施例に限定されるものではない。 Furthermore, although this invention is demonstrated in detail using an Example, this invention is not limited to a following example.
１．Ｓ―アリルグルタチオンによる白血球活性抑制作用の検証
マクロファージを用いてＳ―アリルグルタチオンによる白血球活性抑制作用を検証した。マウスのマクロファージの細胞株であるRAW264.7、及びWistar雄性ラットの肝臓より得られたマクロファージの一種である肝クッパー細胞をそれぞれ培養した。10-12M、10-9M、若しくは10-6MのＳ―アリルグルタチオンを含む培養液、又はＳ―アリルグルタチオンを含まない培養液で24時間培養した後、さらにLPSの存在下で6時間培養して細胞を刺激し、培養上清中のTNF-αの濃度を測定した。
1. Verification of leukocyte activity inhibitory action by S-allyl glutathione The leukocyte activity inhibitory action of S-allyl glutathione was examined using macrophages. RAW264.7, which is a cell line of mouse macrophages, and liver Kupffer cells, which are a kind of macrophages obtained from the livers of Wistar male rats, were cultured. After culturing for 24 hours in a culture solution containing 10 -12 M, 10 -9 M, or 10 -6 M S-allylglutathione or in a culture solution not containing S-allylglutathione, further 6 hours in the presence of LPS The cells were cultured to stimulate the cells, and the concentration of TNF-α in the culture supernatant was measured.
結果を図１に示す。Ｓ―アリルグルタチオンの濃度依存的に低下したことから、Ｓ―アリルグルタチオンはマクロファージの活性抑制作用を有することが明らかとなった。 The results are shown in FIG. Since it decreased depending on the concentration of S-allylglutathione, it was revealed that S-allylglutathione has a macrophage activity inhibitory action.
さらに、Ｓ―アリルグルタチオンが白血球活性化抑制を通じて肝星細胞の活性化を抑制するかどうかを検証した。活性化したマクロファージは肝星細胞を活性化することが知られている。 Furthermore, it was verified whether S-allyl glutathione suppresses activation of hepatic stellate cells through inhibition of leukocyte activation. Activated macrophages are known to activate hepatic stellate cells.
マウスのマクロファージの細胞株であるRAW264.7を、10-12M、10-9M、又は10-6MのＳ―アリルグルタチオンを含む培養液、若しくはＳ―アリルグルタチオンを含まない培養液で24時間培養した後、さらにLPSの存在下で6時間培養して細胞を刺激した。得られた培養上清を１００倍希釈になるように添加して肝星細胞を培養し、肝星細胞の活性化マーカーであるα-SMAの発現をウェスタンブロッティング法により測定した。 RAW264.7, a mouse macrophage cell line, was cultured in a culture solution containing 10 -12 M, 10 -9 M, or 10 -6 M S-allyl glutathione or a culture solution containing no S-allyl glutathione. After culturing for an hour, the cells were further stimulated by culturing for 6 hours in the presence of LPS. The obtained culture supernatant was added at a 100-fold dilution to culture hepatic stellate cells, and the expression of α-SMA, an activation marker for hepatic stellate cells, was measured by Western blotting.
結果を図２に示す。Ｓ―アリルグルタチオン（図中、「SAG」と表示した。）の濃度依存的に肝星細胞の活性化が抑制された。したがって、Ｓ―アリルグルタチオンによりマクロファージの活性が抑制されることで、肝星細胞の活性が抑制されたことが明らかとなった。 The results are shown in FIG. Activation of hepatic stellate cells was suppressed depending on the concentration of S-allylglutathione (indicated as “SAG” in the figure). Therefore, it was revealed that the activity of hepatic stellate cells was suppressed by suppressing the activity of macrophages with S-allylglutathione.
また、肝星細胞におけるコラーゲンＡ１（図中、「ColA1」と表示した。）、及びTGF-βの発現量をRT-PCRによって測定した。コラーゲンＡ１は線維化の指標であり、TGF-βは肝線維化の形成過程に関わっていることが知られている。 In addition, the expression levels of collagen A1 (labeled “ColA1” in the figure) and TGF-β in hepatic stellate cells were measured by RT-PCR. Collagen A1 is an index of fibrosis, and TGF-β is known to be involved in the formation process of liver fibrosis.
結果を図３に示す。図３では、Ｓ―アリルグルタチオン（図中、「SAG」と表示した。）を添加しなかった場合の発現量を100％としてＳ―アリルグルタチオンが発現に与える影響を解析した。LPSでRAW264.7を刺激しなかった場合には、コラーゲンＡ１及びTGF-βの発現は影響が受けなかったが、LPSでRAW264.7を刺激した場合には、コラーゲンＡ１（図３上段）及びTGF-β（図３下段）の発現がＳ―アリルグルタチオンの濃度依存的に減少した。 The results are shown in FIG. In FIG. 3, the effect of S-allyl glutathione on the expression was analyzed with the expression level when S-allyl glutathione (indicated as “SAG” in the figure) was not added as 100%. When RAW264.7 was not stimulated with LPS, the expression of collagen A1 and TGF-β was not affected, but when RAW264.7 was stimulated with LPS, collagen A1 (upper part of FIG. 3) and The expression of TGF-β (lower panel in FIG. 3) decreased depending on the concentration of S-allylglutathione.
以上のことから、Ｓ―アリルグルタチオンにはマクロファージ等の白血球の活性化を抑制する作用を有することが明らかとなった。 From the above, it was revealed that S-allyl glutathione has an action of suppressing the activation of leukocytes such as macrophages.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS504020A (en) * | 1972-06-15 | 1975-01-16 | ||
| JPH02500841A (en) * | 1987-07-09 | 1990-03-22 | オーレンシュレガー，ゲールハルト | Pharmacotherapeutic uses of glutathione derivatives |
| JPH02255624A (en) * | 1989-03-29 | 1990-10-16 | Senjiyu Seiyaku Kk | Platelet coagulation suppressing agent |
| JPH0348626A (en) * | 1989-07-14 | 1991-03-01 | Senjiyu Seiyaku Kk | Anti-inflammatory and/or anti-allergic agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS504020A (en) * | 1972-06-15 | 1975-01-16 | ||
| JPH02500841A (en) * | 1987-07-09 | 1990-03-22 | オーレンシュレガー，ゲールハルト | Pharmacotherapeutic uses of glutathione derivatives |
| JPH02255624A (en) * | 1989-03-29 | 1990-10-16 | Senjiyu Seiyaku Kk | Platelet coagulation suppressing agent |
| JPH0348626A (en) * | 1989-07-14 | 1991-03-01 | Senjiyu Seiyaku Kk | Anti-inflammatory and/or anti-allergic agent |
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