JPWO2006090815A1 - Prion disease prevention agent and food additive and feed additive containing the same - Google Patents
Prion disease prevention agent and food additive and feed additive containing the same Download PDFInfo
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Animal Behavior & Ethology (AREA)
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- Food Science & Technology (AREA)
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Abstract
プリオンすなわち異常プリオン蛋白質により中枢神経系が障害されて発症する神経疾患であり、クロイツフェルト・ヤコブ病（ＣＪＤ）、ゲルストマン・ストロイスラー・シャインカー症候群（ＧＳＳ）、動物のスクレイピーやウシ海綿状脳症（ＢＳＥ）や慢性消耗性疾患（ＣＷＤ）などのプリオン病は、これまでに実質的に有効な治療方法や予防方法が見いだされていない。日常生活において経口摂取している天然食材を用いて、異常プリオン蛋白質の増殖を抑制する効果を有するプリオン病発症予防剤、食品添加剤、飼料添加剤を提供する。プリオン病発症予防剤は、フコイダンを有効成分として含有する。食品添加剤、或いは飼料添加剤は、プリオン病発症予防剤を含む。It is a neurological disease that develops when the central nervous system is damaged by prions, that is, abnormal prion proteins, such as Creutzfeldt-Jakob disease (CJD), Gerstmann-Streisler-Scheinker syndrome (GSS), animal scrapie and bovine spongiform encephalopathy ( For prion diseases such as BSE) and chronic wasting disease (CWD), no effective treatment or prevention method has been found so far. Provided are a prion disease onset preventive agent, a food additive, and a feed additive that have an effect of suppressing the growth of abnormal prion protein using natural foods taken orally in daily life. The prion disease onset preventive agent contains fucoidan as an active ingredient. The food additive or feed additive contains a prion disease onset preventive agent.
Description
本発明は、クロイツフェルト・ヤコブ病、ウシ海綿状脳症など異常プリオン蛋白質に係るプリオン病発症予防剤とそれを含む食品添加剤及び飼料添加剤に関するものである。 The present invention relates to a prion disease onset preventive agent related to abnormal prion proteins such as Creutzfeldt-Jakob disease and bovine spongiform encephalopathy, and a food additive and a feed additive containing the same.
ヒトのクロイツフェルト・ヤコブ病（ＣＪＤ：Ｃｒｅｕｔｚｆｅｌｄｔ Ｊａｋｏｂ Ｄｉｓｅａｓｅ）、ゲルストマン・ストロイスラー・シャインカー症候群（ＧＳＳ：Ｇｅｒｓｔｍａｎｎ−Ｓｔａｕｓｓｌｅｒ−Ｓｃｈｅｉｎｋｅｒ Ｓｙｎｄｒｏｍｅ）、動物のスクレイピーやウシ海綿状脳症（狂牛病、ＢＳＥ：Ｂｏｖｉｎｅ Ｓｐｏｎｇｉｆｏｒｍ Ｅｎｃｅｐｈａｌｏｐａｔｈｙ）や慢性消耗性疾患（ＣＷＤ：Ｃｈｒｏｎｉｃ Ｗａｓｔｉｎｇ Ｄｉｓｅａｓｅ）などのプリオン病は、プリオンと呼ばれる感染性の異常プリオン蛋白質により中枢神経系が障害されて発症するとされる神経疾患であり、これまでに有効な治療方法や予防方法が見いだされていない。 Creutzfeldt-Jakob disease (CJD), Gerstmann-Steisler-Scheinker syndrome (GSJ), animal scrapie and bovine spongiform disease B Prion diseases such as Spongform Encephalopathy (CWD) and chronic wasting disease (CWD) are neurological diseases that are caused by damage to the central nervous system due to an infectious abnormal prion protein called prion. No effective treatment or prevention method has been found.
異常プリオン蛋白質による感染の様式は、詳細には判明していないが、異常プリオン蛋白質は蛋白質でありながら一般的な高圧滅菌、乾燥滅菌によってもその感染性がなくなることがなく、ホルマリンやアルコールなどによって変性不活化されない。従って、現状では異常プリオン蛋白質の増殖を抑えることによってのみ治療や予防が可能であり、これまでにペントサンポリサルフェート、キニーネ類、ライソゾーム親和性薬剤、リアクティブ・ダイ（リアクティブ・グリ−ン、リアクティブ・レッド）〔例えば、特許文献１参照〕、ロイシン、イソロイシン、バリンなど分岐鎖を有する必須アミノ酸、またはトレハロース〔例えば、特許文献２参照〕、キノリン誘導体、またはナフチリジン誘導体〔例えば、特許文献３参照〕などを異常プリオン蛋白質増殖抑制剤として用いることが報告されている。 The type of infection caused by abnormal prion protein is not known in detail, but abnormal prion protein is a protein, but its infectivity is not lost by general high-pressure sterilization or dry sterilization. Denatured and inactivated. Therefore, at present, treatment and prevention are possible only by suppressing the growth of abnormal prion protein. To date, pentosan polysulfate, quinine, lysosomal affinity drugs, reactive dye (reactive green, Active red) (for example, see Patent Document 1), essential amino acids having a branched chain such as leucine, isoleucine, and valine, or trehalose (for example, see Patent Document 2), quinoline derivatives, or naphthyridine derivatives (for example, see Patent Document 3). And the like have been reported to be used as abnormal prion protein growth inhibitors.
一方、本発明は、フコイダンを異常プリオン蛋白質増殖抑制剤として用いることを提案している。フコイダンは、コンブ、ワカメ、モズクなど海藻のヌメリ成分の一つであり、構造としてフコースに硫酸基が結合し、これが数多く連結した硫酸化多糖類である。これまで、フコイダンには、がんの予防としてのアポトーシス誘発剤〔例えば、特許文献４参照〕、創傷治癒促進などの細胞増殖促進剤〔例えば、特許文献５参照〕、免疫強化剤〔例えば、特許文献６参照〕、高脂血症の予防治療剤〔例えば、特許文献７参照〕、悪酔いや二日酔いの予防改善剤〔例えば、特許文献８参照〕、皮膚の弾性維持向上、皮膚肥厚改善を行うコラーゲン産生増強剤〔例えば、特許文献９参照〕などの医薬品として、さらに体重抑制効果と脂肪組織重量、血清中性脂質（トリグリセリド）、低密度リポタンパク、全コレステロール含量を減らす健康食品〔例えば、特許文献１０参照〕、血清中の全コレステロール、中性脂肪を低下させ、ＨＤＬ−コレステロールを増加させ、さらに有用腸内細菌を増加させ便秘解消、美肌促進の効果を有する機能性食品〔例えば、特許文献１１参照〕などの提案があり、医薬品、健康食品としての用途開発が期待されている。 On the other hand, the present invention proposes to use fucoidan as an abnormal prion protein growth inhibitor. Fucoidan is one of the seaweed slime components such as kombu, wakame, mozuku, and is a sulfated polysaccharide with many sulfate groups bonded to fucose as a structure. So far, fucoidan has been used as an apoptosis inducer for preventing cancer (see, for example, Patent Document 4), a cell growth promoting agent for promoting wound healing (see, for example, Patent Document 5), and an immune enhancer (for example, a patent). Reference 6], preventive and therapeutic agent for hyperlipidemia [see, for example, Patent Document 7], preventive / improving agent for hangover and hangover [see, for example, Patent Document 8], collagen for maintaining skin elasticity and improving skin thickening As a pharmaceutical product such as a production enhancer [see, for example, Patent Document 9], further, body weight suppression effect and adipose tissue weight, serum neutral lipid (triglyceride), low density lipoprotein, health food that reduces total cholesterol content [for example, Patent Document 10), lowering total cholesterol and neutral fat in serum, increasing HDL-cholesterol, and further increasing useful intestinal bacteria, relieving constipation, Functional food [for example, see Patent Document 11] having an effect of skin accelerator has proposed such as pharmaceuticals, the use and development of the health food is expected.
上記異常プリオンタンパク質によるプリオン病の社会的問題の深刻化に鑑み、本発明の目的は、日常生活において経口摂取している天然食材を用いて、異常プリオン蛋白質の増殖を抑制する効果を有する食品添加剤、飼料添加剤を提供することにある。 In view of the serious social problem of prion disease caused by the abnormal prion protein, the object of the present invention is to add a food having an effect of suppressing the proliferation of the abnormal prion protein using a natural food taken orally in daily life. It is to provide an agent and a feed additive.
上記目的を達成するため、本発明によるプリオン病発症予防剤は、フコイダンを有効成分として含有することを特徴とする。このプリオン病発症予防剤においては、フコイダンが、海藻よりの抽出物であることが好ましく、また、フコイダンが、オキナワモズクよりの抽出物であることが好適であり、さらに、経口用剤として使用することが良い。 In order to achieve the above object, the prion disease prevention agent according to the present invention is characterized by containing fucoidan as an active ingredient. In this prion disease prevention agent, fucoidan is preferably an extract from seaweed, and fucoidan is preferably an extract from Okinawa mozuku, and further used as an oral preparation. That is good.
そして、本発明による食品添加剤は、上述のようなプリオン病発症予防剤を含むことを特徴としており、また、本発明による飼料添加剤は、上述のようなプリオン病発症予防剤を含むことを特徴とするものである。 The food additive according to the present invention is characterized by containing the prion disease onset preventive agent as described above, and the feed additive according to the present invention contains the above prion disease onset preventive agent. It is a feature.
本発明によりプリオン病の発症を防止又は遅らせることが出来、しかも日常食している天然物を素材としていることから、副作用の心配のないプリオン病の発症予防食材、発症予防動物飼料が実現される。 According to the present invention, the onset of prion disease can be prevented or delayed, and since the natural product that is eaten daily is used as a raw material, the prion disease prevention food and the onset prevention animal feed without side effects are realized.
本発明のプリオン病発症予防剤は、フコイダンを有効成分として含有している。本発明は、さらにこのプリオン病発症予防剤を含む食品添加剤、飼料添加剤であるが、ここで、食品添加剤は人が食する食品に添加されるもの、飼料添加剤は動物が食する飼料に添加されるものである。 The prion disease onset preventive agent of the present invention contains fucoidan as an active ingredient. The present invention further includes a food additive and a feed additive containing the prion disease onset preventive agent. Here, the food additive is added to food eaten by humans, and the feed additive is eaten by an animal. It is added to the feed.
ここで、プリオン病は、人におけるクロイツフェルト・ヤコブ病、ゲルストマン・ストロイスラー・シャインカー症候群、致死性家族性不眠症など、牛、羊、鹿などの動物におけるスクレイピー、牛海綿状脳症（ＢＳＥ）、慢性消耗性疾患など異常プリオン蛋白質増殖による疾患である。 Here, prion diseases include Creutzfeldt-Jakob disease, Gerstmann-Streisler-Scheinker syndrome, fatal familial insomnia, scrapie in cattle, sheep, deer and other animals, bovine spongiform encephalopathy (BSE) It is a disease caused by abnormal prion protein proliferation such as chronic debilitating disease.
本発明の有効成分であるフコイダンは、前述したようにコンブ、ワカメ、モズクなど海藻に多く含まれる成分であり、化学的にはフコースに硫酸基が結合し、これが数多く連結した硫酸化多糖類である。本発明で用いるフコイダンは、その採取源を限定するものではないが、好ましくはコンブ、ワカメ、モズクなど海藻類（褐藻類）、さらに好ましくはオキナワモズク（学名；Ｃｌａｄｏｓｉｐｈｏｎ ｏｋａｍｕｒａｎｕｓ Ｔｏｋｉｄａ）より抽出される。 As described above, fucoidan, which is an active ingredient of the present invention, is a component that is abundant in seaweed such as kombu, wakame, mozuku, and is a sulfated polysaccharide in which sulfate groups are chemically linked to fucose and many of them are linked. is there. The fucoidan used in the present invention is not limited in its collection source, but is preferably extracted from seaweeds (brown algae) such as kombu, wakame and mozuku, and more preferably from Okinawa mozuku (scientific name: Cladosiphon okamuranus Tokida).
フコイダンは、海藻類抽出物として精製され粉体となるが、本発明のプリオン病発症予防剤は精製粉体であっても抽出液の液状濃縮物であってもよい。この精製粉体あるいは抽出液状濃縮物をそのまま、あるいは錠剤、粉末製剤（散剤）、顆粒剤、液剤などとして経口摂取される。摂取量は、症状、目的や意図する効果等によって異なり一律に限定し得ない。フコイダンは、各種機能性食品、健康食品などとして市販されており、それ自体有害なものではないので、大量に摂取しても実害はない。 Fucoidan is purified as a seaweed extract into powder, but the prion disease prevention agent of the present invention may be a purified powder or a liquid concentrate of the extract. The purified powder or extracted liquid concentrate is taken orally as it is or as a tablet, powder preparation (powder), granule, liquid or the like. The intake varies depending on symptoms, purpose, intended effect, etc., and cannot be uniformly limited. Fucoidan is marketed as various functional foods, health foods, and the like and is not harmful per se, so there is no real harm even if it is consumed in large quantities.
また、このプリオン病発症予防剤は、人が食する食品に添加しても動物が食する飼料に添加してもよい。この場合の添加量は、人あるいは動物における上記プリオン病発症予防剤の摂取量と食品あるいは飼料の量とを考慮して決められる。 Moreover, this prion disease onset preventive agent may be added to foods eaten by humans or feeds eaten by animals. The addition amount in this case is determined in consideration of the intake of the above-mentioned prion disease onset preventive agent and the amount of food or feed in humans or animals.
１）フコイダン
（株）トロピカルテクノセンターから分与されたオキナワモズク由来の低分子画分フコイダン粉末（Ｌ−ＦＫ粉末）及び高分子画分フコイダン粉末（Ｈ−ＦＫ粉末）を用いた。これらのＦＫ粉末は、表１に示すような品質を有しており、また、無菌粉末ではないが、一般細菌数、大腸菌数、カビ・酵母数について、食品衛生検査指針、微生物編２００４に適合することが確認されている。1) Fucoidan A low molecular fraction fucoidan powder (L-FK powder) and a high molecular fraction fucoidan powder (H-FK powder) derived from Okinawa Mozuku distributed from Tropical Techno Center Co., Ltd. were used. These FK powders have the qualities shown in Table 1 and are not sterile powders, but conform to the Food Sanitation Inspection Guidelines and Microorganisms 2004 regarding the number of general bacteria, E. coli, and mold / yeast. It has been confirmed that
〔抗プリオン効果のｉｎ ｖｉｔｒｏ評価〕
表１に示した低分子画分フコイダン粉末（Ｌ−ＦＫ粉末）及び高分子画分フコイダン粉末（Ｈ−ＦＫ粉末）につき、プリオン持続感染細胞を用いるＩｓｈｉｋａｗａ，Ｄｏｈ−ｕｒａらの検定評価法〔Ｋｅｎｓｕｋｅ Ｉｓｈｉｋａｗａ，Ｋａｔｓｕｍｉ Ｄｏｈ−ｕｒａ，ｅｔ ａｌ．，Ｊｏｕｒｎａｌ ｏｆ Ｇｅｎｅｒａｌ Ｖｉｒｏｌｏｇｙ（２００４），Ｖｏｌ．８５，ｐｐ１７８５−１７９０〕に準じ、抗プリオン効果のｉｎ ｖｉｔｒｏ評価を行った。ここでは、プリオン持続感染細胞として、ＳｃＮ２ａ細胞：スクレイピープリオンであるＲＭＬ株が持続感染した神経芽細胞腫細胞（Ｎ２ａ）、及びＦ−３細胞：ＧＳＳ患者由来プリオンである福岡１株が持続感染したマウス型プリオン蛋白を過剰発現した神経芽細胞腫細胞（Ｎ２ａ＃５８）、の２種類の細胞を用い、それぞれコンフルエントに生えた細胞数の１０分の１を新たなフラスコ内に継代する際に、Ｌ−ＦＫ粉末、又はＨ−ＦＫ粉末の水溶液を以下に示す各種濃度となるよう培養液に加え、３．５日間培養した。培地（培養液）として、１０％胎児牛血清添加ＭＥＭ（Ｏｐｔｉ−ＭＥＭ、Ｇｉｂｃｏ−ＢＲＬ社製）を用い、Ｌ−ＦＫ又はＨ−ＦＫの培養液中添加濃度は、１、２．５、５、７．５、１０μｇ／ｍＬ、又は、０．０１、０．１、１、１０、１００μｇ／ｍＬとした。次に、それぞれコンフルエントとなった細胞をリン酸緩衝生理食塩液（ＰＢＳ）で洗浄した後、細胞溶解バッファー〔０．５％ポリオキシエチレン−ｐ−オクチルフェノール（商品名ＮＰ−４０）及び０．５％デオキシコール酸ナトリウム添加ＰＢＳ〕で細胞を溶解し、溶解液を軽遠心して核酸成分を除いた後に、プロティナーゼＫ（ｐｒｏｔｅｉｎａｓｅ Ｋ）を１０μｇ／ｍＬとなるように加え、３７℃で３０分間消化した。この消化液にフェニルメタンスルホニルフルオライド（ＰＭＳＦ）を０．００１Ｍとなるように加え酵素反応を止めた。その後、超遠心（４１５０００×ｇ、４℃、３０分間）にて異常型プリオン蛋白を沈査として回収し、ウエスタンブロット法にてプリオン蛋白を解析した。ウエスタンブロット法による試験結果は、ＳｃＮ２ａ細胞を用いた場合についてドデシル硫酸ナトリウム加ポリアクリルアミドゲル電気泳動（ＳＤＳ−ＰＡＧＥ）の泳動像を図１に、Ｆ−３細胞を用いた場合についてのＳＤＳ−ＰＡＧＥ泳動像を図２に示したとおり、Ｌ−ＦＫ、Ｈ−ＦＫ共に、培地への添加濃度に依存して異常型プリオン蛋白の産生を阻害することが確認された。また、異常型プリオン蛋白の産生を５０％阻害する濃度（ＩＣ５０）を求め、この結果を表２に示した。[In vitro evaluation of anti-prion effect]
For the low molecular fraction fucoidan powder (L-FK powder) and the high molecular fraction fucoidan powder (H-FK powder) shown in Table 1, the assay evaluation method [Kensuke of Ishikawa, Doh-ura et al. Ishikawa, Katsumi Doh-ura, et al. , Journal of General Virology (2004), Vol. 85, pp 1785-1790], an in vitro evaluation of the anti-prion effect was performed. Here, as a prion persistently infected cell, ScN2a cell: neuroblastoma cell (N2a) persistently infected with RML strain which is scrapie prion, and F-3 cell: Fukuoka 1 strain which is a prion derived from GSS patient were persistently infected. When two types of cells, neuroblastoma cells (N2a # 58) overexpressing mouse prion protein, are used, and 1/10 of the number of confluent cells is subcultured into a new flask. Then, an aqueous solution of L-FK powder or H-FK powder was added to the culture solution so as to have various concentrations shown below, followed by culturing for 3.5 days. As a medium (culture solution), 10% fetal calf serum-added MEM (Opti-MEM, manufactured by Gibco-BRL) was used, and the concentration of L-FK or H-FK added in the culture solution was 1, 2.5, 5 7.5, 10 μg / mL, or 0.01, 0.1, 1, 10, 100 μg / mL. Next, after each confluent cell was washed with phosphate buffered saline (PBS), cell lysis buffer [0.5% polyoxyethylene-p-octylphenol (trade name NP-40) and 0.5 The cells were lysed with PBS containing% sodium deoxycholate], and the lysate was lightly centrifuged to remove nucleic acid components, and then proteinase K (proteinase K) was added to 10 μg / mL and digested at 37 ° C. for 30 minutes. . To this digested solution, phenylmethanesulfonyl fluoride (PMSF) was added to a concentration of 0.001 M to stop the enzymatic reaction. Thereafter, the abnormal prion protein was recovered as a precipitate by ultracentrifugation (415000 × g, 4 ° C., 30 minutes), and the prion protein was analyzed by Western blotting. The results of the Western blot test are shown in Fig. 1 for the electrophoresis of sodium dodecyl sulfate-added polyacrylamide gel electrophoresis (SDS-PAGE) when using ScN2a cells, and SDS-PAGE when using F-3 cells. As shown in FIG. 2, it was confirmed that both L-FK and H-FK inhibit the production of abnormal prion protein depending on the concentration added to the medium. Further, the concentration (IC50) that inhibits the production of abnormal prion protein by 50% was determined, and the results are shown in Table 2.
〔抗プリオン効果のｉｎ ｖｉｖｏ評価（Ｉ−１）〕
高分子画分フコイダン粉末（Ｈ−ＦＫ粉末）につき、Ｔｇ７マウス（ハムスター型プリオン蛋白を過剰発現した遺伝子改変マウス）と２６３Ｋ（ハムスターで継代されているスクレイピーのプリオン株）脳ホモジネートを用いるＤｏｈ−ｕｒａ，Ｉｓｈｉｋａｗａらの検定評価法〔Ｋａｔｓｕｍｉ Ｄｏｈ−ｕｒａ，Ｋｅｎｓｕｋｅ Ｉｓｈｉｋａｗａ，ｅｔ ａｌ．，Ｊｏｕｒｎａｌ ｏｆ Ｖｉｒｏｌｏｇｙ（２００４），Ｖｏｌ．７８，ｐｐ４９９９−５００６〕に準じ、抗プリオン効果のｉｎ ｖｉｖｏ評価を行った。ここでは、生理食塩水で１％（Ｗ／Ｖ）濃度とした２６３Ｋ脳ホモジネートに、Ｈ−ＦＫ粉末を添加混合し、それぞれ０．０２、０．２、２、２０、２００（μｇ／２０μＬ）のＨ−ＦＫ濃度とした感染材料をＴｇ７マウスの脳内に２０μＬづつ投与し、脳内感染させた。Ｔｇ７マウスは８週齢以上で各群内で雌雄がほぼ同数となるように調整し、脳内感染から死亡するまでの潜伏期間を測定した。この結果は、表３及び図３に示すとおりである。また、一元配置分散分析（ｏｎｅ−ｗａｙ ＡＮＯＶＡ）及びチュキィ−クレイマー法（Ｔｕｋｅｙ−Ｋｒａｍｅｒ法）による多重比較検定を行った結果、フコイダン（Ｈ−ＦＫ）を２００μｇ／２０μＬ添加混合した群は、対照群に比して有意（ｐ＜０．０５）な潜伏期間延長を示すことが確認された。[In vivo evaluation of anti-prion effect (I-1)]
Doh- using high molecular fraction fucoidan powder (H-FK powder) using Tg7 mouse (gene modified mouse overexpressing hamster prion protein) and 263K (scrapie prion strain passaged in hamster) brain homogenate ura, Ishikawa et al. [Katsumi Doh-ura, Kensuke Ishikawa, et al. , Journal of Virology (2004), Vol. 78, pp 4999-5006], an in vivo evaluation of the anti-prion effect was performed. Here, H-FK powder was added to and mixed with 263K brain homogenate adjusted to 1% (W / V) with physiological saline, and 0.02, 0.2, 2, 20, and 200 (μg / 20 μL), respectively. Infectious material having an H-FK concentration of 20 μL was administered into the brain of Tg7 mice at a time to cause infection in the brain. Tg7 mice were adjusted to have approximately the same number of males and females in each group at 8 weeks of age or older, and the incubation period from brain infection until death was measured. The results are as shown in Table 3 and FIG. In addition, as a result of performing a multiple comparison test by one-way analysis of variance (one-way ANOVA) and Tukey-Kramer method (Tukey-Kramer method), a group in which fucoidan (H-FK) was added and mixed at 200 μg / 20 μL was a control group It was confirmed that the incubation period was significantly prolonged (p <0.05) compared to.
〔抗プリオン効果のｉｎ ｖｉｖｏ評価（Ｉ−２）〕
感染材料として、１％２６３Ｋ脳ホモジネートに替えて、生理食塩水で０．１％（Ｗ／Ｖ）濃度とした２６３Ｋ脳ホモジネート（０．１％２６３Ｋ脳ホモジネート）を用い、Ｈ−ＦＫ粉末を添加混合し、室温にて一晩放置した後、Ｔｇ７マウスに脳内感染させた以外は、抗プリオン効果のｉｎ ｖｉｖｏ評価（Ｉ−１）の場合と同様にｉｎ ｖｉｖｏ評価を行った。この結果は、表４及び図４に示すとおりである。また、一元配置分散分析（ｏｎｅ−ｗａｙ ＡＮＯＶＡ）及びチュキィ−クレイマー法による多重比較検定を行った結果、フコイダン（Ｈ−ＦＫ）を２００μｇ／２０μＬ添加混合した群は、対照群やフコイダン（Ｈ−ＦＫ）を０．０２μｇ／２０μＬ添加混合した群に比して有意（ｐ＜０．０１）な潜伏期間延長を示すことが確認された。[In vivo evaluation of anti-prion effect (I-2)]
Instead of 1% 263K brain homogenate, 263K brain homogenate (0.1% 263K brain homogenate) with physiological saline was used instead of 1% 263K brain homogenate, and H-FK powder was added. After mixing and allowing to stand overnight at room temperature, in vivo evaluation was performed in the same manner as in in vivo evaluation of anti-prion effect (I-1) except that Tg7 mice were infected in the brain. The results are as shown in Table 4 and FIG. In addition, as a result of conducting a one-way analysis of variance (one-way ANOVA) and a multiple comparison test by the Tukey-Kramer method, a group in which 200 μg / 20 μL of fucoidan (H-FK) was added and mixed was a control group or fucoidan (H-FK ) Was confirmed to show a significant (p <0.01) incubation period extension as compared to the group added with 0.02 μg / 20 μL.
〔抗プリオン効果のｉｎ ｖｉｖｏ評価（ＩＩ）〕
マウス飼育用の一般粉末飼料（ＭＦ、オリエンタル酵母工業社製）に、２．５％、５％、１０％（Ｗ／Ｗ）となるように飼料添加剤としてフコイダン（Ｈ−ＦＫ粉末）を添加混合しフコイダン添加飼料を調製した。また、生理食塩水で１０％（Ｗ／Ｖ）濃度とした２６３Ｋ脳ホモジネート（１０％２６３Ｋ脳ホモジネート）２００μＬを経口ゾンデを用い、Ｔｇ７マウスの胃内に投与することにより経口感染させた。このような経口感染モデルマウスに対し、（ｉ）経口感染直前までの６日間、又は（ｉｉ）経口感染直後より６日間、各濃度のフコイダン添加飼料を餌として与えた。フコイダン無添加飼料を餌として与えた対照を含めて、一匹あたりの一日餌摂取量は４〜６ｇであった。Ｔｇ７マウスは８週齢以上で各群内で雌雄がほぼ同数となるように調整し、経口感染から死亡するまでの潜伏期間を測定した。この結果は、表５及び図５に示すとおりである。また、一元配置分散分析（ｏｎｅ−ｗａｙ ＡＮＯＶＡ）及びチュキィ−クレイマー法による多重比較検定を行った結果、経口感染後にフコイダン添加飼料を経口摂取した群は、対照（フコイダン非摂取）群や感染前摂取群に比して有意（ｐ＜０．０１）な潜伏期間延長を示すことが確認された。なお、フコイダン経口摂取量（２．５％、５％、１０％）の間に有意差は認められなかった。[In vivo evaluation of anti-prion effect (II)]
Add fucoidan (H-FK powder) as feed additive to general powdered feed for mice breeding (MF, manufactured by Oriental Yeast Co., Ltd.) to be 2.5%, 5%, 10% (W / W) A mixed feed containing fucoidan was prepared. Further, 200 μL of 263K brain homogenate (10% 263K brain homogenate) adjusted to a concentration of 10% (W / V) with physiological saline was used for oral infection by administration into the stomach of Tg7 mice using an oral sonde. Such oral infection model mice were fed with diets supplemented with fucoidan at various concentrations for (i) 6 days immediately before oral infection, or (ii) 6 days immediately after oral infection. Including the control fed with fucoidan-free diet, the daily food intake per animal was 4-6 g. Tg7 mice were 8 weeks of age or older and adjusted so that there were approximately the same number of males and females in each group, and the incubation period from oral infection to death was measured. The results are as shown in Table 5 and FIG. In addition, as a result of performing a multiple comparison test by one-way analysis of variance (one-way ANOVA) and the Tukey-Kramer method, the group that orally ingested the fucoidan-added feed after oral infection is the control (no fucoidan ingestion) group or the pre-infection intake It was confirmed to show a significant (p <0.01) latency period extension compared to the group. There was no significant difference between fucoidan oral intake (2.5%, 5%, 10%).
本発明によりプリオン病の発症を遅らせることが出来、牛においては食肉の安全性が確保され、人においては社会生活を営むに支障ない期間が延長されて福祉的にも社会経済的にも利することが多い。 According to the present invention, the onset of prion disease can be delayed, the safety of meat is ensured in cattle, and in humans, the period that does not interfere with social life is extended, which is beneficial for welfare and socioeconomic reasons. There are many cases.
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| PCT/JP2006/303370 WO2006090815A1 (en) | 2005-02-25 | 2006-02-24 | Agent for preventing development of prion disease, food additive and feed additive comprising the same |
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| JP2003040778A (en) * | 2001-07-27 | 2003-02-13 | Sangaku Renkei Kiko Kyushu:Kk | Composition for inhibiting production of pathological prion protein and method for inhibiting production of pathological prion protein |
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