JP6075830B2 - Trpv4活性抑制剤 - Google Patents
Trpv4活性抑制剤 Download PDFInfo
- Publication number
- JP6075830B2 JP6075830B2 JP2012167587A JP2012167587A JP6075830B2 JP 6075830 B2 JP6075830 B2 JP 6075830B2 JP 2012167587 A JP2012167587 A JP 2012167587A JP 2012167587 A JP2012167587 A JP 2012167587A JP 6075830 B2 JP6075830 B2 JP 6075830B2
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- JP
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- Prior art keywords
- acid
- trpv4
- chlorogenic acids
- caffeic acid
- salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
したがって、TRPV4の活性化を抑制することにより、尿意の増加及び排尿頻度の増加を特徴とする過活動膀胱に治療効果をもたらすと考えられる。
しかし、クロロゲン酸類やカフェ酸がTRPV4活性抑制作用を有することや過活動膀胱の予防、改善に有用であることは知られていない。
また本発明は、クロロゲン酸類、カフェ酸及びそれらの塩から選ばれる1種以上を有効成分とする過活動膀胱の予防又は改善剤に係るものである。
本発明におけるクロロゲン酸類には、具体的には、3−カフェイルキナ酸、4−カフェイルキナ酸、5−カフェイルキナ酸、3,4−ジカフェイルキナ酸、3,5−ジカフェイルキナ酸、4,5−ジカフェイルキナ酸、3−フェルリルキナ酸、4−フェルリルキナ酸、5−フェルリルキナ酸及び3−フェルリル−4−カフェイルキナ酸等が含まれる(中林ら,コーヒー焙煎の化学と技術,弘学出版株式会社,p166-167)。
本発明においては、これらの塩を調製してから、その他の成分からなる組成物中に添加したものでもよいし、クロロゲン酸類等と塩形成成分とを別々に該組成物中に添加して、この中で塩を形成せしめたものでもよい。
例えば、クロロゲン酸類は、コーヒー生豆、南天の葉、リンゴ未熟果等の植物体から抽出したものが好ましく、さらにアカネ科コーヒー(Coffee arabica LINNE)の種子より、温時アスコルビン酸、クエン酸酸性水溶液又は熱水で抽出して得たものがより好ましい。
また、食品としては、TRPV4活性抑制、過活動膀胱の予防又は改善等の生理機能をコンセプトとし、必要に応じてその旨を表示した飲食品、機能性飲食品、病者用飲食品、特定保健用食品等を包含する。
このような種々の剤型の医薬製剤は、クロロゲン酸類、カフェ酸又はそれらの塩を単独で、又は他の薬学的に許容される賦形剤、結合剤、増量剤、崩壊剤、界面活性剤、滑沢剤、分散剤、緩衝剤、保存剤、嬌味剤、香料、被膜剤、担体、希釈剤等を適宜組み合わせることにより調製することができる。
種々の形態の食品は、クロロゲン酸類、カフェ酸又はそれらの塩を単独で、又は他の食品材料や、溶剤、軟化剤、油、乳化剤、防腐剤、香科、安定剤、着色剤、酸化防止剤、保湿剤、増粘剤等を適宜組み合わせることにより調製することができる。当該食品中のクロロゲン酸類、カフェ酸又はそれらの塩の含有量(抽出物の乾燥物換算)は、通常0.001質量%以上、好ましくは0.005質量%以上、より好ましくは0.01質量%以上であり、そして、10質量%以下、好ましくは5質量%以下、より好ましくは1質量%以下である。例えば、0.001〜10質量%、好ましくは0.005〜5質量%、より好ましく0.01〜1質量%が挙げられる。
<1>クロロゲン酸類、カフェ酸及びそれらの塩から選ばれる1種以上を有効成分とするTRPV4活性抑制剤。
<2>クロロゲン酸類、カフェ酸及びそれらの塩から選ばれる1種以上を有効成分とする過活動膀胱の予防又は改善剤。
<4>過活動膀胱及び間質性膀胱炎から選ばれる膀胱障害の予防又は改善剤を製造するための、クロロゲン酸類、カフェ酸及びそれらの塩から選ばれる1種以上の使用。
<5>TRPV4活性抑制に使用するためのクロロゲン酸類、カフェ酸及びそれらの塩から選ばれる1種以上。
<6>過活動膀胱及び間質性膀胱炎から選ばれる膀胱障害の予防又は改善に使用するためのクロロゲン酸類、カフェ酸及びそれらの塩から選ばれる1種以上。
<7>クロロゲン酸類、カフェ酸及びそれらの塩から選ばれる1種以上を、それらを必要とする対象に投与又は摂取するTRPV4活性抑制方法。
<8>クロロゲン酸類、カフェ酸及びそれらの塩から選ばれる1種以上を、それらを必要とする対象に投与又は摂取する過活動膀胱の予防又は改善方法。
<9>非治療的な方法である前記<7>〜<8>の方法。
ヒト十二指腸由来細胞株であるHutu−80細胞(American Type Culture Collectionより購入)から抽出したtotalRNAを逆転写して得られたcDNAを鋳型にして、公開されているヒトTRPV4遺伝子配列を参考に合成した、下記に示す塩基配列で表されるオリゴヌクレオチドからなるプライマーセットを用いて、下記の条件下でポリメラーゼ連鎖反応(PCR)を行った。
フォワードプライマー;5’-CACCATGGCGGATTCCAGCGAAGGCCC-3’:配列番号1
リバースプライマー;5’-CTAGAGCGGGGCGTCATCAGTCC-3’:配列番号2
a) PCR溶液組成
cDNA(Template) 15μl
5x PrimeStar GXL Buffer 10μl
dNTPs mixture (2.5mM) 4μl
PrimeStar GXL DNA Polymerase (タカラバイオ) 1μl
Forward Primer (10μM) 1μl
Reverse Primer (10μM) 1μl
Water 18μl
b) 温度とサイクル条件
95℃ 2min
↓
98℃ 10sec 33 cycles
70℃ 2min
10%牛胎児血清を含むDMEM/F12培地(インビトロジェン)を用いてHEK293細胞(American Type Culture Collectionより購入)の培養を行った。HEK293細胞をT−75細胞培養用フラスコに5×105cells/Flaskで播種した。培養3日後、参考例1で作製したヒトTRPV4発現ベクター(8μg)をTransIT−293(Mirus)を用いて細胞にトランスフェクションし1日培養した。Detachin(Genlantis)で細胞をはがし96well Optical bottom plate (Nunc)に10%牛胎児血清を含むDMEM/F12培地で1.5×104cells/90μl/wellの細胞密度で播き、さらに1日培養した。
(数1)
阻害率(%)=〔 (F300C1/F0C1−F300/F0)/(F300C1/F0C1−F300C2/F0C2) 〕x 100
F300 ;測定開始300秒後のGSK1016790aと検体を添加したウェルの蛍光強度
F300C1;測定開始300秒後のGSK1016790aとDMSOを添加したウェルの蛍光強度
F300C2;測定開始300秒後のDMSOのみを添加したウェルの蛍光強度
F0 ;測定開始直後のGSK1016790aと検体を添加したウェルの蛍光強度
F0C1 ;測定開始直後のGSK1016790aとDMSOを添加したウェルの蛍光強度
F0C2 ;測定開始直後のDMSOのみを添加したウェルの蛍光強度
コントロールであるDMSOの阻害率を0%とした時、コントロールに対する検体の阻害率をDunnetにより検定した。結果を表1に示す。
表1より、コントロールに比べて、クロロゲン酸、カフェ酸は300μMでTRPV4活性を有意に阻害した。
Claims (2)
- クロロゲン酸類、カフェ酸及びそれらの塩から選ばれる1種以上を有効成分とするTRPV4活性抑制剤であって、
クロロゲン酸類が3−カフェイルキナ酸、4−カフェイルキナ酸、5−カフェイルキナ酸、3−フェルリルキナ酸、4−フェルリルキナ酸、及び5−フェルリルキナ酸から選ばれる1種以上である、TRPV4活性抑制剤。 - クロロゲン酸類、カフェ酸及びそれらの塩から選ばれる1種以上を有効成分とする過活動膀胱の予防又は改善剤であって、
クロロゲン酸類が3−カフェイルキナ酸、4−カフェイルキナ酸、5−カフェイルキナ酸、3−フェルリルキナ酸、4−フェルリルキナ酸、及び5−フェルリルキナ酸から選ばれる1種以上である、過活動膀胱の予防又は改善剤。
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