JP2021038147A - Mitochondrial biosynthesis promoter - Google Patents
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Abstract
Description
本発明はミトコンドリア生合成促進剤に関する。 The present invention relates to a mitochondrial biosynthesis promoter.
ＡＴＰ産生の主たる場であるミトコンドリアは、加齢や細胞酸素ラジカル、ある種の薬物、糖尿病や肥満など代謝疾患などで減少し、原病態の進行、重症化に働くことが判明し、治療の最大標的となっている。 Mitochondria, which are the main site of ATP production, are reduced due to aging, cellular oxygen radicals, certain drugs, metabolic diseases such as diabetes and obesity, etc. It is a target.
特許文献１には、ヒドロキシチロソールとカフェイン等とを含む組成物がミトコンドリア生合成を促進させることが記載されているが、現在のところ、ミトコンドリアの増殖ないし活性化の有効な方法としては、エクササイズ、カロリー摂取制限などが中心であり、治療や簡便で現実的な方法・手段を欠いているのが現況である。 Patent Document 1 describes that a composition containing hydroxytyrosol and caffeine promotes mitochondrial biosynthesis, but at present, as an effective method for mitochondrial proliferation or activation, there is an effective method for mitochondrial proliferation or activation. The current situation is that exercise and calorie intake restriction are the main focus, and there is a lack of treatment and simple and practical methods and means.
一方、１，５−Ｄ−アンヒドロフルクトース（以下、場合により「１，５−ＡＦ」と称する）は、ある種の子嚢菌や紅藻由来の酵素であるα−１，４−グルカンリアーゼを澱粉又は澱粉分解物に作用させることで生産することができる。１，５−ＡＦは、その分子間内に二重結合を有しており、他の単糖類と比較して反応性に富む糖である。 On the other hand, 1,5-D-anhydrofructose (hereinafter, sometimes referred to as "1,5-AF") contains α-1,4-glucan lyase, which is an enzyme derived from certain ascomycetes and red algae. It can be produced by acting on starch or starch decomposition products. 1,5-AF is a sugar that has a double bond between its molecules and is highly reactive as compared with other monosaccharides.
従来、１，５−ＡＦの様々な用途が知られている。例えば、特許文献２は、１，５−ＡＦ及び／又はその脱水産物であるアスコピロンを含有する抗腫瘍剤を、特許文献３は、１，５−ＡＦを有効成分として含有する、アポトーシス関連スペック様カード蛋白質（ＡＳＣ）の機能阻害薬及びＡＳＣが関与する疾患又は症状の治療薬、並びに１，５−ＡＦを有効成分として含有するインフラマソーム経路阻害薬及びインフラマソーム経路が関与する疾患又は症状の治療薬を、特許文献４は、１，５−ＡＦを有効成分として含有する細胞老化抑制剤を開示する。 Conventionally, various uses of 1,5-AF are known. For example, Patent Document 2 contains an antitumor agent containing 1,5-AF and / or its dehydrated product, ascopylone, and Patent Document 3 contains 1,5-AF as an active ingredient. Card protein (ASC) function inhibitors and therapeutic agents for ASC-related diseases or symptoms, as well as inframasome pathway inhibitors and inframasome pathway-related diseases or symptoms containing 1,5-AF as an active ingredient. Patent Document 4 discloses a cell senescence inhibitor containing 1,5-AF as an active ingredient.
しかしながら、１，５−ＡＦとミトコンドリア生合成促進活性との関係についてはこれまで報告されていない。 However, the relationship between 1,5-AF and mitochondrial biosynthesis promoting activity has not been reported so far.
本発明は、１，５−ＡＦの新たな用途を提供することを目的とする。 An object of the present invention is to provide a new use of 1,5-AF.
本発明者らは、前記課題を解決すべく鋭意研究を行った結果、１，５−ＡＦがミトコンドリア生合成促進（mitochondria biogenesis）活性を有することを見出し、本発明を完成するに至った。 As a result of diligent research to solve the above problems, the present inventors have found that 1,5-AF has mitochondria biogenesis-promoting activity, and have completed the present invention.
すなわち、本発明の要旨は以下のとおりである。
（１）１，５−アンヒドロフルクトースを有効成分として含有するミトコンドリア生合成促進剤。
（２）ＰＧＣ１−αを介してミトコンドリア数を増加させるための前記（１）に記載のミトコンドリア生合成促進剤。
（３）ミトコンドリアの数的減少又は質的機能障害に起因する病態又は疾患の治療又は予防剤である前記（１）又は（２）に記載のミトコンドリア生合成促進剤。
（４）ミトコンドリアの数的減少又は質的機能障害に起因する病態又は疾患が白内障、網膜色素変性症、聴力低下、心筋症、不整脈、肝機能低下、ザルコペニア、筋力低下、骨粗しょう症及び敗血症性ショックから選ばれる前記（３）に記載のミトコンドリア生合成促進剤。
That is, the gist of the present invention is as follows.
(1) A mitochondrial biosynthesis promoter containing 1,5-anhydrofructose as an active ingredient.
(2) The mitochondrial biosynthesis promoter according to (1) above for increasing the number of mitochondria via PGC1-α.
(3) The mitochondrial biosynthesis promoter according to (1) or (2) above, which is a therapeutic or preventive agent for a pathological condition or disease caused by a decrease in the number of mitochondria or qualitative dysfunction.
(4) Pathological conditions or diseases caused by mitochondrial decrease in number or qualitative dysfunction are cataract, retinitis pigmentosa, hearing loss, cardiomyopathy, arrhythmia, liver dysfunction, zarkopenia, muscle weakness, osteoporosis and septic shock. The mitochondrial biosynthesis promoter according to (3) above, which is selected from shock.
本発明によれば、ミトコンドリアの生合成を促進させることにより、ミトコンドリアの数的減少又は質的機能障害に起因する病態又は疾患を治療又は予防することができる。 According to the present invention, by promoting the biosynthesis of mitochondria, it is possible to treat or prevent a pathological condition or disease caused by a numerical decrease or qualitative dysfunction of mitochondria.
以下、本発明を詳細に説明する。
本発明のミトコンドリア生合成促進剤は１，５−ＡＦを有効成分として含有するものである。
Hereinafter, the present invention will be described in detail.
The mitochondrial biosynthesis promoter of the present invention contains 1,5-AF as an active ingredient.
ミトコンドリアは体内の赤血球以外の諸細胞のエネルギー（ＡＴＰ）産生に関わる重要な細胞内小器官である。従って、ミトコンドリアの量的減少、質的障害、機能不全は、全身各細胞臓器に広いスペクトラムの病態、機能不全を惹起する。 Mitochondria are important organelles involved in the production of energy (ATP) in cells other than red blood cells in the body. Therefore, quantitative reduction of mitochondria, qualitative disorders, and dysfunction cause a wide spectrum of pathological conditions and dysfunctions in each cell organ throughout the body.
本発明のミトコンドリア生合成促進剤は、ミトコンドリアの生合成を促進させることにより、ミトコンドリアの数的減少又は質的機能障害に起因する病態又は疾患を治療又は予防することができる。 The mitochondrial biosynthesis promoter of the present invention can treat or prevent a pathological condition or disease caused by a numerical decrease or qualitative dysfunction of mitochondria by promoting mitochondrial biosynthesis.
前記のミトコンドリアの数的減少又は質的機能障害に起因する病態又は疾患としては、例えば白内障、網膜色素変性症、聴力低下、心筋症、不整脈、肝機能低下、ザルコペニア（筋委縮症）、筋力低下、骨粗しょう症、敗血症性ショックが挙げられる。 The pathological conditions or diseases caused by the numerical decrease or qualitative dysfunction of mitochondria include, for example, cataract, retinitis pigmentosa, hearing loss, cardiomyopathy, arrhythmia, liver dysfunction, zarcopenia (muscle atrophy), and muscle weakness. , Osteoporosis, septic shock.
本発明のミトコンドリア生合成促進剤における有効成分である１，５−ＡＦは、例えば特表平９−５０５９８８号公報（「１，５−Ｄ−アンヒドロフルクトース調製のためのα−１，４−グルカンリアーゼの使用」）に記載の方法等の公知の方法に準じて調製することができる。 1,5-AF, which is the active ingredient in the mitochondrial biosynthesis promoter of the present invention, is described in, for example, JP-A-9-505988 (“α-1,4- for the preparation of 1,5-D-anhydrofructose”). It can be prepared according to a known method such as the method described in "Use of glucan lyase").
本発明のミトコンドリア生合成促進剤は、安定でそれ以上の変化を受けないため、有効成分である１，５−ＡＦ以外に、例えば製剤担体、賦形剤、水溶化剤、安定剤等、その他の製剤や製品を添加することも可能である。 Since the mitochondrial biosynthesis promoter of the present invention is stable and does not undergo any further changes, in addition to the active ingredients 1,5-AF, for example, preparation carriers, excipients, water-soluble agents, stabilizers, etc. It is also possible to add the above-mentioned preparations and products.
また、本発明のミトコンドリア生合成促進剤は、医薬品、医薬部外品、健康食品、特定保健用食品として使用することができ、あるいは飲食品等に配合することもできる。 In addition, the mitochondrial biosynthesis promoter of the present invention can be used as a pharmaceutical product, a quasi-drug, a health food, a food for specified health use, or can be blended in foods and drinks.
本発明のミトコンドリア生合成促進剤は、その剤形に応じてそれ自体公知の種々の方法で投与することが可能であり、その投与量、投与部位、投与する間隔、期間等は、患者の年齢や体重、病状あるいは他の薬剤や治療法と併用した場合等を考慮して適宜決定することができる。投与方法としては、特に制限されないが、例えば、経口投与、注射や点滴静注、あるいは噴霧、軟膏等の形での局所投与等が挙げられる。 The mitochondrial biosynthesis promoter of the present invention can be administered by various methods known per se depending on its dosage form, and its dose, administration site, administration interval, period, etc. are the age of the patient. It can be appropriately determined in consideration of the body weight, medical condition, and the case of combined use with other drugs and treatment methods. The administration method is not particularly limited, and examples thereof include oral administration, injection, intravenous drip infusion, and local administration in the form of spray, ointment, or the like.
本発明のミトコンドリア生合成促進剤の投与量は、その剤形、投与方法、又は治療しようとする症状により異なるが、例えば、患者の体重１ｋｇ当たりの投与量として有効成分（１，５−ＡＦ）換算で１〜５００ｍｇ、好ましくは１０〜１００ｍｇとすることができ、１日１回又は数回、あるいは持続点滴等、更には数日毎に１回というような、適当な投与頻度によって投与することが可能である。 The dose of the mitochondrial biosynthesis promoter of the present invention varies depending on the dosage form, administration method, or symptomatology to be treated, and is, for example, the active ingredient (1,5-AF) as the dose per 1 kg of the patient's body weight. It can be converted to 1 to 500 mg, preferably 10 to 100 mg, and may be administered at an appropriate administration frequency such as once or several times a day, continuous infusion, or even once every few days. It is possible.
本発明のミトコンドリア生合成促進剤の剤形としては、例えば散剤、顆粒剤、細粒剤、カプセル剤（例えば、粉末入りカプセル剤）、錠剤、液剤、注射剤、点滴剤、噴霧剤、軟膏剤等が挙げられるが、特に制限されない。 Dosage forms of the mitochondrial biosynthesis promoter of the present invention include, for example, powders, granules, fine granules, capsules (for example, capsules containing powder), tablets, liquids, injections, infusions, sprays, ointments. Etc., but are not particularly limited.
以下、実施例を用いて本発明をより詳細に説明するが、本発明の技術的範囲はこれら実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the technical scope of the present invention is not limited to these Examples.
（実施例１）
神経細胞株ＰＣ１２を、培養皿培養面の約８０％に占めるまで培養し、ミトコンドリア障害剤ロテノン（Rotenone）を無機化合物溶解剤ＤＭＳＯ（ジメチルスルホキシド）で溶解し、ロテノン（終濃度１μＭ）を添加して２４時間培養した。
(Example 1)
The nerve cell line PC12 is cultured until it occupies about 80% of the culture surface of the culture dish, the mitochondrial damage agent rotenone is dissolved with the inorganic compound solubilizer DMSO (dimethyl sulfoxide), and rotenone (final concentration 1 μM) is added. Was cultured for 24 hours.
蛍光顕微鏡用の蛍光標識色素で細胞中のミトコンドリアを選択的に標識できるミトトラッカー（Mito Tracker）を用いた蛍光顕微鏡写真を図１に示す。実際に細胞数をＭＴＴ法で測定し、定量化したものが図２の棒グラフ図である。 FIG. 1 shows a fluorescence micrograph using a Mito Tracker capable of selectively labeling mitochondria in cells with a fluorescence labeling dye for a fluorescence microscope. The bar graph of FIG. 2 shows the actual number of cells measured by the MTT method and quantified.
図１のａ．はＤＭＳＯのみ、ｂ．はそれに１，５−ＡＦを５０μｇ／ｍｌ添加したコントロールを示す。図１のブルーは核、赤紫色はミトコンドリアを示す。 FIG. 1 a. Is DMSO only, b. Indicates a control to which 50 μg / ml of 1,5-AF was added. In FIG. 1, blue indicates a nucleus and magenta indicates a mitochondria.
図１の下段は培養神経細胞株ＰＣ１２にミトコンドリア障害剤であるロテノンを添加して、細胞への影響を観察したものであるが、ｃ．のロテノン添加によりミトコンドリア染色（ミトトラッカーの赤紫色）が減少している。しかしながら、ｄ．に示すように１，５−ＡＦ添加群では赤紫色染色が強くなって、１，５−ＡＦのミトコンドリア保護とそれを介した細胞毒性の軽減がみられた。 The lower part of FIG. 1 shows the effect on cells by adding rotenone, which is a mitochondrial disorder agent, to the cultured nerve cell line PC12. Mitochondrial staining (purple of mitochondria) is reduced by the addition of rotenone. However, d. As shown in the above, in the 1,5-AF-added group, the magenta staining became stronger, and mitochondrial protection of 1,5-AF and reduction of cytotoxicity mediated by the mitochondrial protection were observed.
すなわち、ロテノンは神経細胞株ＰＣ１２のミトコンドリアを障害して減少させたが（図１ｃ）、１，５−ＡＦ添加はそれをブロックした（図１ｄ）。図１の上段のａ．及びｂ．はロテノンを溶解していないＤＭＳＯコントロールを示す。ロテノンによるミトコンドリアの減少は、１，５−ＡＦで有意にブロックされている（図２、右図の右バー）。 That is, rotenone damaged and reduced the mitochondria of neuronal cell line PC12 (Fig. 1c), but addition of 1,5-AF blocked it (Fig. 1d). The upper part of FIG. 1 a. And b. Indicates a DMSO control in which rotenone is not dissolved. The reduction of mitochondria by rotenone is significantly blocked at 1,5-AF (Fig. 2, right bar in the right figure).
生細胞を染色するのに適した蛍光染色色素であるカルセイン−ＡＭを用いた蛍光顕微鏡写真を図３に、対応する定量図（実際に細胞数をカウントした図（キーエンス顕微鏡下、ｎ＝３））を図４に示す。なお、カルセイン−ＡＭ自体は非蛍光性であり、生細胞の膜を容易に通過し、細胞質で細胞内エステラーゼによって膜不透過性、緑色蛍光のカルセインへと加水分解される。 A fluorescence micrograph using calcein-AM, which is a fluorescence staining dye suitable for staining living cells, is shown in FIG. 3, and a corresponding quantitative diagram (a diagram in which the number of cells is actually counted (Keyence microscope, n = 3)). ) Is shown in FIG. Calcein-AM itself is non-fluorescent, easily passes through the membrane of living cells, and is hydrolyzed in the cytoplasm to membrane-impermeable, green-fluorescent calcein by intracellular esterase.
図３から、神経細胞株ＰＣ１２を２４時間ロテノン処理すると細胞数が減少している（シャーレ内緑色の面積で示されている。ロテノンのミトコンドリア障害による）ことがわかる（上２つの図はＤＭＳＯコントロール）。下段の顕微鏡図（４図）がロテノン添加によるミトコンドリア障害を介した細胞数減少に対する１，５−ＡＦ添加（０、１０、５０、１００μｇ／ｍｌ）の効果を示す。図４は、１，５−ＡＦ処理（０、１０、５０、１００μｇ／ｍｌ）すると、濃度依存的にロテノンの細胞障害性が軽減されていることを定量化したものである。１，５−ＡＦ添加で濃度依存的に細胞数（カルセイン染色、緑色）が増加した（緑色の範囲拡大）。 From FIG. 3, it can be seen that the number of cells decreased when the nerve cell line PC12 was treated with rotenone for 24 hours (indicated by the green area in the petri dish, due to the mitochondrial damage of rotenone) (the upper two figures are DMSO controls). ). The lower microscopic view (Fig. 4) shows the effect of 1,5-AF addition (0, 10, 50, 100 μg / ml) on the decrease in cell number mediated by mitochondrial damage due to rotenone addition. FIG. 4 quantifies that the cytotoxicity of rotenone is reduced in a concentration-dependent manner by 1,5-AF treatment (0, 10, 50, 100 μg / ml). The addition of 1,5-AF increased the number of cells (calcane staining, green) in a concentration-dependent manner (expansion of the range of green).
ＡＭＰＫの下流にはＰＧＣ１αが位置し、ＡＭＰＫ活性化により、ＰＧＣ１αが活性化され、ミトコンドリア新生が惹起される。５−ＡＦ処理により、ＰＧＣ１αからのミトコンドリア形成（mitochondriogenesis）の経路が活性化されて、ロテノン障害は軽減される。この経路が活性化されてミトコンドリア障害が防止されていることは、ＰＧＣ１αのアンチセンスｍＲＮＡ（ｓｉＲＮＡ）処理ではロテノン障害がブロックされたのに対し、コントロールのｓｉＲＮＡ処理では、ロテノンによる細胞障害が抑制されず、細胞数が減少したことからも示された。 PGC1α is located downstream of AMPK, and AMPK activation activates PGC1α and induces mitochondrial neoplasia. 5-AF treatment activates the mitochondrialogenesis pathway from PGC1α and reduces rotenone damage. The activation of this pathway to prevent mitochondrial damage means that PGC1α antisense mRNA (siRNA) treatment blocked rotenone damage, whereas control siRNA treatment suppressed rotenone-induced cell damage. It was also shown by the decrease in the number of cells.
（実施例２）
ＡＭＰＫの下流にはミトコンドリアの新生に関わる転写因子ＰＧＣ１αが存在するので、１，５−ＡＦはメトホルミンと同じく、ＰＧＣ１αを介して、ロテノンによるミトコンドリア障害・減少と細胞減少をブロックしているものと結論される。このことはＰＧＣ１αの発現をアンチセンスｍＲＮＡ（ｓｉＲＮＡ）で抑制すると、ロテノンの細胞障害活性は回避しえず、細胞数減少が誘導されている（図５左）のに対し、コントロール（ＰＧＣ１α抑制活性のないｓｉＲＮＡ処理）では、ロテノン処理による細胞数の減少が観察され、１，５−ＡＦ、メトホルミン（ｍｅｔ）の効果が消失されていることから証明された（図５右）。
(Example 2)
Since the transcription factor PGC1α involved in mitochondrial neoplasia exists downstream of AMPK, it was concluded that 1,5-AF, like metformin, blocks mitochondrial damage / reduction and cell loss due to rotenone via PGC1α. Will be done. This is because when the expression of PGC1α is suppressed by antisense mRNA (siRNA), the cytotoxic activity of rotenone cannot be avoided and the decrease in the number of cells is induced (Fig. 5, left), whereas the control (PGC1α inhibitory activity). In the case of siRNA treatment without siRNA), a decrease in the number of cells due to rotenone treatment was observed, which was proved by the disappearance of the effects of 1,5-AF and metformin (met) (Fig. 5, right).
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