JP7007705B2 - Protective agent against neurodegeneration - Google Patents
Protective agent against neurodegeneration Download PDFInfo
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- JP7007705B2 JP7007705B2 JP2017152754A JP2017152754A JP7007705B2 JP 7007705 B2 JP7007705 B2 JP 7007705B2 JP 2017152754 A JP2017152754 A JP 2017152754A JP 2017152754 A JP2017152754 A JP 2017152754A JP 7007705 B2 JP7007705 B2 JP 7007705B2
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Description
特許法第３０条第２項適用 平成２９年３月１８日にアクロス福岡で開催された「第６７回日本木材学会大会」で発表Application of Article 30, Paragraph 2 of the Patent Law Presented at the "67th Annual Meeting of the Wood Society of Japan" held at Acros Fukuoka on March 18, 2017.
本発明は、神経変性に対する保護剤に関する。より詳細には、アミロイドベータペプチド（Ａβ）の蓄積による神経変性に対する保護剤に関する。 The present invention relates to a protective agent against neurodegenerative diseases. More specifically, it relates to a protective agent against neurodegenerative diseases due to accumulation of amyloid beta peptide (Aβ).
近年、高齢化社会の到来とともに認知症患者が増加している。認知症のほとんどは、神経変性疾患であるアルツハイマー病（ＡＤ）によるものであり、ＡＤはＡβの蓄積によって誘発されることが知られている。従って、Ａβの蓄積による神経変性に対する保護剤の研究開発が盛んに行われているが（例えば特許文献１）、ＡＤの予防方法や治療方法は、今なお確立されるには至っていない。 In recent years, the number of dementia patients has been increasing with the advent of an aging society. Most of the dementia is caused by Alzheimer's disease (AD), which is a neurodegenerative disease, and it is known that AD is induced by the accumulation of Aβ. Therefore, although research and development of a protective agent against neurodegeneration due to accumulation of Aβ has been actively carried out (for example, Patent Document 1), a preventive method and a therapeutic method for AD have not yet been established.
そこで本発明は、Ａβの蓄積による神経変性に対する保護剤を提供することを目的とする。 Therefore, an object of the present invention is to provide a protective agent against neurodegeneration due to accumulation of Aβ.
本発明者らは上記の点に鑑みて鋭意検討を行った結果、スギの樹皮に含まれる揮発性抗菌成分として知られているフェルギノール（ｆｅｒｒｕｇｉｎｏｌ）が、Ａβの蓄積による神経変性に対する保護作用を有することを見出した。 As a result of diligent studies in view of the above points, the present inventors have found that ferruginol, which is known as a volatile antibacterial component contained in the bark of Sugi, has a protective effect against neurodegeneration due to the accumulation of Aβ. I found that.
上記の知見に基づいてなされた本発明のＡβの蓄積による神経変性に対する保護剤は、請求項１記載の通り、フェルギノールまたはその薬学的に許容される塩を有効成分とする。 As described in claim 1, the protective agent for neurodegeneration caused by the accumulation of Aβ of the present invention made based on the above findings contains ferruginol or a pharmaceutically acceptable salt thereof as an active ingredient.
本発明によれば、Ａβの蓄積による神経変性に対する保護剤を提供することができる。 According to the present invention, it is possible to provide a protective agent against neurodegeneration due to accumulation of Aβ.
本発明の神経変性に対する保護剤は、フェルギノールまたはその薬学的に許容される塩を有効成分とするものである。 The protective agent against neurodegeneration of the present invention contains ferruginol or a pharmaceutically acceptable salt thereof as an active ingredient.
本発明において用いるフェルギノールは、スギの樹皮に含まれる揮発性抗菌成分として知られているアビエタン系のジテルペノイドであり、下記の化学構造を有する（小藤田久義ら、木材学会誌 Ｖｏｌ．４７，Ｎｏ．６，ｐ．４７９－４８６（２００１））。 Ferruginol used in the present invention is an abietane-based diterpenoid known as a volatile antibacterial component contained in the bark of Sugi, and has the following chemical structure (Hisayoshi Kofujita et al., Journal of the Wood Society Vol. 47, No. 6, p.479-486 (2001)).
本発明において用いるフェルギノールは、例えば、スギの樹皮を原料として、ヘキサン、酢酸エチル、クロロホルム、アセトン、アルコール（メタノールやエタノールやイソプロパノールなど）などの有機溶媒を用いた抽出操作、シリカゲルカラムクロマトグラフィーや高速液体クロマトグラフィーなどを用いた分離操作、減圧濃縮操作などを組み合わせて行うことで、取得することができる。フェルギノールは、単離精製されたものに限定されず、フェルギノールを含む溶媒抽出物や精油などの形態で用いてもよい。また、本発明において用いるフェルギノールは、有機化学的手法で合成されたものであってもよい。フェルギノールの薬学的に許容される塩としては、ナトリウム塩やカリウム塩などのアルカリ金属塩などを例示することができる。 The ferginol used in the present invention is, for example, an extraction operation using the bark of cedar as a raw material and an organic solvent such as hexane, ethyl acetate, chloroform, acetone, alcohol (methanol, ethanol, isopropanol, etc.), silica gel column chromatography, and high performance liquid chromatography. It can be obtained by performing a separation operation using liquid chromatography or the like, a vacuum concentration operation, or the like in combination. Ferruginol is not limited to isolated and purified ones, and may be used in the form of a solvent extract containing ferruginol, an essential oil, or the like. Further, the ferruginol used in the present invention may be synthesized by an organic chemical method. Examples of the pharmaceutically acceptable salt of ferruginol include alkali metal salts such as sodium salt and potassium salt.
本発明の神経変性に対する保護剤は、各種の製剤形態に製剤化することでそれ自体を医薬品や健康食品として服用や摂取することができることに加え、各種の飲食品に配合して摂取することで、ＡＤの予防剤や治療剤としての効果が期待できる。その適用量は、適用者の年齢や体重、症状の程度、適用形態などによって異なるが、特に制限されるものではない。また、本発明の神経変性に対する保護剤は、その有効成分であるフェルギノールが揮発性を有することから、経鼻的吸入によるアロマセラピー的用法で用いることもできる。この適用形態は、これまでにないＡＤの予防方法や治療方法として期待される。 The protective agent against neurodegenerative disease of the present invention can be taken or ingested as a drug or health food by formulating it into various pharmaceutical forms, and can also be ingested by blending it with various foods and drinks. , It can be expected to be effective as a preventive or therapeutic agent for AD. The amount to be applied varies depending on the age and weight of the person to be applied, the degree of symptoms, the form of application, and the like, but is not particularly limited. In addition, the protective agent against neurodegeneration of the present invention can also be used in aromatherapy by nasal inhalation because ferruginol, which is an active ingredient thereof, has volatile properties. This application form is expected as an unprecedented preventive method and therapeutic method for AD.
以下、本発明を実施例によって詳細に説明するが、本発明は以下の記載に限定して解釈されるものではない。 Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not construed as being limited to the following description.
実施例１：フェルギノールのＡβの蓄積による神経変性に対する保護作用
小藤田久義ら、木材学会誌 Ｖｏｌ．４７，Ｎｏ．６，ｐ．４７９－４８６（２００１）に記載の方法に従って、スギの樹皮の粉末からヘキサン抽出物を得、その分画を、シリカゲルカラムクロマトグラフィーと高速液体クロマトグラフィー（順相および逆相）を用いて行い、減圧濃縮して単離精製した、白色粉末のフェルギノール（マススペクトル、核磁気共鳴スペクトル、旋光度を文献値と比較することにより同定）を被験物質として、以下の実験を行った。
Example 1: Protective effect of ferruginol on neurodegeneration by accumulation of Aβ Hisayoshi Kofujita et al., Journal of the Wood Society Vol. 47, No. 6, p. Hexane extracts were obtained from cedar bark powder according to the method described in 479-486 (2001) and fractions thereof were performed using silica gel column chromatography and high performance liquid chromatography (forward and reverse phase). The following experiments were carried out using a white powder of ferginol (identified by comparing the mass spectrum, nuclear magnetic resonance spectrum, and luminosity with the literature values), which was isolated and purified by concentration under reduced pressure, as a test substance.
（実験方法）
ヒトＡβ遺伝子が導入されたトランスジェニック線虫（Ｃ．ｅｌｅｇａｎｓ ＣＬ４１７６系統）を用いて調べた。この線虫は、２５℃において筋組織特異的にヒトＡβが発現して蓄積し、麻痺状態をもたらす。この際、被験物質を共存させ、麻痺状態が抑制されるか否かを観察することで、被験物質のＡβの蓄積による神経変性に対する保護作用の有無を知ることができる（Ｗｕ，Ｙ．ら、Ｃｕｒｒｅｎｔ Ａｌｚｈｅｉｍｅｒ Ｒｅｓｅａｒｃｈ，２，３７（２００５））。直径５２ｍｍの試験用プレートに、被験物質としてのフェルギノール５μｇを含むＤＭＳＯ溶液１０μＬを、線虫のエサとなる大腸菌（ＯＰ５０株の２４時間培養物）１０μＬとともに滴下・塗布した後、大腸菌を２５℃で２４時間増殖させてから、別に１６℃で飼育した線虫（Ｌ３幼虫）５０匹を移した。その後、２５℃で線虫を飼育することで、経時的に麻痺状態になった個体数を追跡した。なお、ポジティブコントロールには、市販のギンコライドＡ（５μｇ）を用い、上記と同様の方法で、経時的に麻痺状態になった個体数を追跡した。
(experimental method)
Transgenic nematodes into which the human Aβ gene was introduced ( C. elegans CL4176 strain) were used for examination. This nematode expresses and accumulates human Aβ in a muscle tissue-specific manner at 25 ° C, resulting in a paralyzed state. At this time, by coexisting the test substance and observing whether or not the paralyzed state is suppressed, it is possible to know whether or not the test substance has a protective effect against neurodegeneration due to the accumulation of Aβ (Wu, Y. et al., Et al. Current Alzheimer Research, 2,37 (2005)). 10 μL of DMSO solution containing 5 μg of ferruginol as a test substance was dropped and applied to a test plate having a diameter of 52 mm together with 10 μL of Escherichia coli (24-hour culture of OP50 strain) used as food for nematodes, and then Escherichia coli was added dropwise at 25 ° C. After growing for 24 hours, 50 nematodes (L3 larvae) bred separately at 16 ° C. were transferred. Then, by breeding nematodes at 25 ° C., the number of individuals paralyzed over time was tracked. A commercially available ginkgolide A (5 μg) was used as a positive control, and the number of individuals who became paralyzed over time was followed by the same method as described above.
（実験結果）
Ａβの蓄積によってもたらされる麻痺状態にならなかった個体数の経時的変化を図１に示す。図１から明らかなように、フェルギノールは、ギンコライドＡと同程度のＡβの蓄積による神経変性に対する保護作用を有することがわかった。
(Experimental result)
FIG. 1 shows the change over time in the number of individuals who did not become paralyzed due to the accumulation of Aβ. As is clear from FIG. 1, ferruginol was found to have a protective effect against neurodegeneration by accumulating Aβ to the same extent as ginkgolide A.
製剤例１：錠剤
以下の成分組成からなる神経変性に対する保護のための錠剤を自体公知の方法で製造した。
フェルギノール １
乳糖 ８０
ステアリン酸マグネシウム １９ （単位：重量％）
Formulation Example 1: Tablet A tablet for protection against neurodegeneration having the following component composition was produced by a method known per se.
Ferruginol 1
Lactose 80
Magnesium stearate 19 (Unit:% by weight)
製剤例２：ビスケット
以下の成分組成からなる神経変性に対する保護のためのビスケットを自体公知の方法で製造した。
フェルギノール １
薄力粉 ３２
全卵 １６
バター １６
砂糖 ２４
水 １０
ベーキングパウダー １ （単位：重量％）
Preparation Example 2: Biscuits Biscuits for protection against neurodegenerative diseases having the following composition were produced by a method known per se.
Ferruginol 1
Whole egg 16
Butter 16
Sugar 24
Water 10
Baking powder 1 (Unit:% by weight)
本発明は、Ａβの蓄積による神経変性に対する保護剤を提供することができる点において、産業上の利用可能性を有する。 The present invention has industrial applicability in that it can provide a protective agent against neurodegenerative diseases due to the accumulation of Aβ.
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| KR101516362B1 (en) * | 2009-05-04 | 2015-05-04 | 엘지전자 주식회사 | Induction heating device |
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| JP2015044768A (en) | 2013-08-28 | 2015-03-12 | 国立大学法人岩手大学 | Alpha wave promoter |
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| KR101516362B1 (en) * | 2009-05-04 | 2015-05-04 | 엘지전자 주식회사 | Induction heating device |
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