JP2022511785A - 認知症を処置するための組成物および方法 - Google Patents
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Abstract
Description
本出願は、2018年11月28日出願の米国仮特許出願62/772,211の利益および優先権を主張し、この全内容は引用により本明細書に包含される。
本発明は、認知症を処置する方法に関する。
からなる群から選択される、一つまたはそれ以上の活性成分としての化合物を含む。
特に定義されていない限り、本明細書で使用されているすべての技術用語および科学用語は、本発明が属する技術分野の当業者が一般的に理解しているものと同じ意味を有する。
1.材料
BrdU、ギ酸およびThioflavin Sは、Sigma-Aldrich(St Louis, MO, USA)から購入した。一般的な化学製品は、Sigma-Aldrich(St Louis, MO, USA)またはMerck(Darmstadt, Germany)から購入した。
ARH003は、皿で培養されているベニクスノキタケから調製した。子実体(300g)およびARH004は、切断木で培養されているベニクスノキタケ(ARH004)から調製した。子実体を、95%エタノールで熱還流した。エタノール溶液を真空に濃縮し、褐色の抽出物(60g)を得た。
国家中医学研究所の機関内動物保護および使用委員会承認の動物プロトコール(IACUC No:106-417-4)。動物とその保護に関するすべての実験操作は、米国国立衛生研究所(United States National Institutes of Health, NIH)により発行された実験動物のケアと使用に関するガイドに従って実施した。APP/PS1は、Jackson試験室(No.005864)から購入した。飼育の性比は、一つのケージに1匹の雄性と2匹の雌性であった。野生型のシブリング(sibling)マウスとADトランスジェニックの雌性C57BL/6Jマウスを用いて実験を行った。動物は、室温(24±1℃)および湿度(55~65%)、12:12時間(07:00~19:00)の明暗周期下で管理された環境で飼育した。すべての動物実験操作は、実験動物の保護と使用に関するガイド(NIH)に基づいて実施した。APP/PS1は、Jackson試験室(No.005864)から購入した。雌性トランスジェニックマウスおよび雄性野生型のシブリングを用いて飼育した。動物は、温度(24±1℃)および湿度(55~65%)下で飼育した。明暗周期は、12:12時間(07:00~19:00)にした。すべてのマウスに、市販の齧歯類用の普通の餌、および自由引水を提供した。治療効果を研究するために、3ヶ月齢の雄性および雌性のAPP/PS1マウスの両方に、ビヒクル(n=7 雄性およびn=8 雌性)またはARH003もしくはARH004(100mg kg-1日-1、n=7 雄性およびn=10 雌性)を4ヶ月間経口胃管栄養法(oral gavage)で投与した。
マウスを、麻酔をかけた後、経心食塩水の灌流で犠牲にした。マウスの脳を摘出し、4℃下、4%ホルムアルデヒドに一晩浸し、凍結保護した。続いて、脳組織を30μmの厚さに切った。各脳において、頭蓋骨の前項を大体-1.58から-1.82に跨る3枚のスライドを、染色と分析に使用した。
線維性アミロイドの染色は、メーカー(Biosensis Inc., Thebarton, South Australia)の説明に従ってAmylo-Gloを用いて行った
先に述べたように、免疫組織化学を行った(39)。簡単に説明すると、切片を、1%ウシ血清アルブミン(BSA)、3%正常ロバ血清、0.3%Triton X-100を含有するリン酸緩衝化食塩水(PBS)で1時間ブロックした。その後、4℃下で以下の物質を含有するPBS中でインキュベートした:1%BSA、1%正常ロバ血清、0.3%Triton X-100、ならびにAβ1-16に対するマウスモノクローナル抗体(AB10, Millipore, MAB5208, 2757889)、およびグリア線維酸性タンパク質に対するウスモノクローナル抗体(GFAP, Millipore, MAB5804, 1990686)を含む一次抗体;ならびに抗イオン化カルシウム結合アダプター分子-1(Iba-1)抗体に対するヤギポリクローナル抗体(abcam, ab5076, GR268568-3)。続いて、切片を室温で、Hoechst33258(Invitrogen, 2μg ml-1)、フルオレセインイソチオシアネートまたはrhodamine red X(RRX)共役ロバ抗マウスIgG、RRX共役ロバ抗ウサギIgGまたはAlexa Fluor 647共役ロバ抗ヤギIgG(Jackson ImmunoResearch, 705-605-147)を含有する抗体希釈緩衝液中で2時間インキュベートした。0.01%Triton X-100を含有するPBSで洗浄した後、切片をAqua Poly/Mount(Polyscience Inc., Warrington, PA, USA)にはめ込み、Zeiss LSM 780共焦点顕微鏡(Jena, Germany)を用いて顕微鏡的分析を行った。体表的な共焦点画像は、最大投射で10μm深さであった。ImageJソフトウェアを用いてアミロイドプラークの定量化を行った。総面積に対するAB10-反応性またはThS陽性面積の比によってアミロイドプラークの負荷を計算した。
マウスを、70日間の強制経口投与後、前記のように(46)、穴掘りテストの評価を行い、若干の補正を加えた。要するに、70日目に群ケージで練習を行い、77日目と80日目には個別テストを行った。マウスを、薄層の床敷を備えた新しいケージで飼育し、続いて翌日の16:00時に餌ペレット230gを含むシリンダーをケージに入れた。最後に、2時間後と一晩後にシリンダー内に残った餌ペレットの重量を測定した。2回目の個別テストでは、餌ペレットに対する穴掘りにおける2時の測定を結果に示した。
90日間の処理後、前記のように(41,42)、モリス水迷路(MWM)テストを用いて空間記憶パホーマンスを評価し、若干の修正を加えた。要するに、水迷路装置は、直径120cm、深さ40cmの円形プールからなっており、プラットフォーム(直径10cm)を覆うように水(温度22~24℃)を20cmの高さまで入れた。無毒の白色の塗料を追加することにより、プラットフォームを不透明な水の表面から1cm下に沈ませた。記述的なデータ収集について、プールを四つの等しい象限概念的に分けた。コンピューター化ビデオ画像解析システム(Ethovision, Noldus Information Technology Inc, USA)を用いて、迷路の白色の背景における黒色のマウスの水泳経路を記録した。
結果は平均値±平均標準誤差(SEM)で表し、GraphPad Prism 5ソフトウェアを用いて統計分析処理した。パラメトリックなデータは、対になっていない両側スチューデントのt検定(unpaired two-tailed Student's t-test)、または一元配置分散分析(ANOVA)とpost-hoc Bonferroni's多重比較検定によってパラメトリックデータを分析した。Kruskal-Wallis ANOVAとその後のpost hoc Dunnett's多重比較検定を用いて、MWM試験でのプラットフォームの横断時間、穴掘りテストにおける餌ペレットの量、巣作りテストにおける巣作りスコアなどのノンパラメトリックデータを分析した。
HPLCクロマトグラフィーを用いてARH003およびARH004の分子特性を決定
本研究で用いられたベニクスノキタケ子実体は、クスノキ属牛楠(Cinnamomum kanehirae)木で栽培されたベニクスノキタケ子実体と高い植物相類似性指数(phytomic similarity index)を有する皿で培養されている(ARH003)である(Chung et al, 2016)。この類似性を確認するために、HPLCクロマトグラフィーを用いて、皿で培養されているベニクスノキタケ(ARH003)と切断木で培養されているベニクスノキタケ(ARH004)との成分を比較した(図1)。
ARH003は、APP/PS1マウスの大脳中のAβプラークを減少させた。
6ヶ月齢のAPP/PS1マウスでプラークが見られることは十分に確立されている(23)。したがって、3ヶ月齢のAPP/PS1雄雌または雌性マウスに、ビヒクルまたは100mg kg-1日-1のARH003を4ヶ月間経口投与し、Aβプラークの沈着(deposition)とグリア細胞の活性化に対するARH003の効果を研究した。ARH003投与中の体重変化を調査したところ、雄性マウスでは投与最終月にARH003が体重を有意に増加させたが、雌性マウスでは増加させなかった(図2)。
ARH003は、APP/PS1マウスの大脳中のグリア集団(glial cluster)を有するプラークの数を減少させる。
グリア集団を有するプラークの数に対するARH003の効果を評価した。APP/PS1トランスジェニックマウスの大脳中のグリア集団を有するプラークを判定するために、Amylo-glo染色、Iba-1およびGFAP免疫染色によって、Aβプラーク、ミクログリアおよびアストロサイトをそれぞれ検査した。その結果、ARH003で処置後、グリア集団を有するプラークの数が減少することがわかった(図3A~3E)。
ARH003は、APP/PS1マウスの認知低下を回復させた。
穴掘り行動や巣作り行動は、脳の幅広い領域に作用し、これまでADトランスジェニックマウスのADLスキルの評価に応用されてきた。本研究では、3ヶ月齢のAPP/PS1マウスにARH003(100mg kg-1日)を114日間経口投与した。続いて、経口投与後84日目および86日目に穴掘りおよび巣作りのタスクを開始した(図4A)。APP/PS1マウスでは、自然発症穴掘り行動に欠陥が見られたが、ARH003を投与することで有意に回復した。APP/PS1マウスはまた、巣作りスコアと細断されていないネストレットによって評価された巣作り行動に欠陥が見られた。ARH003の投与により、障害された巣作り行動が有意に回復した(図4B)。
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Claims (12)
- 認知症のための医薬を製造するための、ベニクスノキタケ子実体の抽出物の使用。
- ベニクスノキタケ子実体の抽出物が、皿で培養されているその子実体の抽出物である、請求項1に記載の使用。
- ベニクスノキタケ子実体の抽出物が、切断木で培養されているその子実体の抽出物である、請求項1に記載の使用。
- ベニクスノキタケ子実体の抽出物が、ベニクスノキタケ子実体を水または有機溶媒で抽出することによって調製される、請求項1に記載の使用。
- 有機溶媒が、エタノールである、請求項4に記載の使用。
- 認知症が、アルツハイマー病(AD)である、請求項1~7のいずれか一項に記載の使用。
- 抽出物が、Aβプラーク沈着およびグリア細胞の活性化の抑制に有効である、請求項1~5のいずれか一項に記載の使用。
- 抽出物が、記憶障害の改善に有効である、請求項1~5のいずれか一項に記載の使用。
- 化合物が、Aβプラーク沈着およびグリア細胞の活性化の抑制に有効である、請求項6~7のいずれか一項に記載の使用。
- 化合物が、記憶障害の改善に有効である、請求項6~7のいずれか一項に記載の使用。
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EP (1) | EP3886862A4 (ja) |
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AU (1) | AU2019387473A1 (ja) |
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CN113350360A (zh) * | 2021-06-18 | 2021-09-07 | 西南医科大学 | 一种三萜酸类化合物作为Aβ纤维形成抑制剂药物的新用途 |
TWI779875B (zh) * | 2021-10-13 | 2022-10-01 | 健裕生技股份有限公司 | 預防神經受損及保護神經的化合物、其製法、醫藥品及其用途 |
US11987566B2 (en) | 2022-01-28 | 2024-05-21 | Genhealth Pharma Co., Ltd. | Nerve damage preventing and nerve protecting compounds, preparation method thereof, pharmaceutical composition thereof, and their use |
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US7601854B2 (en) * | 2006-10-25 | 2009-10-13 | Kang Jian Biotech Corp., Ltd. | Diterpenes from the fruiting body of Antrodia camphorata and pharmaceutical compositions thereof |
BR112015011798A2 (pt) * | 2012-11-21 | 2017-07-11 | Golden Biotechnology Corp | métodos e composições para tratar doenças neurodegenerativas |
TWI623749B (zh) * | 2015-04-30 | 2018-05-11 | 吳永昌 | 一種樟芝萃取物製備及分析方法 |
TW201733573A (zh) * | 2016-03-25 | 2017-10-01 | Ying-Yu Guo | 牛樟芝化合物用於製備治療及預防神經退行性疾病之藥物的用途 |
CN107296805A (zh) * | 2016-04-14 | 2017-10-27 | 郭盈妤 | 牛樟芝化合物及其萃取物用于制备治疗及预防神经退行性疾病的药物的用途 |
CN106727898B (zh) * | 2017-02-21 | 2020-07-31 | 阮时宝 | 一种防治阿尔茨海默病的药物组合物及其制备方法 |
TW202038981A (zh) * | 2018-11-28 | 2020-11-01 | 薩摩亞商吉亞生技控股股份有限公司 | 治療失智症的組合物及方法 |
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- 2019-11-29 AU AU2019387473A patent/AU2019387473A1/en active Pending
- 2019-11-29 CN CN201980077854.0A patent/CN113453689A/zh active Pending
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