JP5931633B2 - Trpv4活性抑制剤 - Google Patents
Trpv4活性抑制剤 Download PDFInfo
- Publication number
- JP5931633B2 JP5931633B2 JP2012167586A JP2012167586A JP5931633B2 JP 5931633 B2 JP5931633 B2 JP 5931633B2 JP 2012167586 A JP2012167586 A JP 2012167586A JP 2012167586 A JP2012167586 A JP 2012167586A JP 5931633 B2 JP5931633 B2 JP 5931633B2
- Authority
- JP
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- Prior art keywords
- trpv4
- ferulic acid
- salt
- activity
- activity inhibitor
- 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、フェルラ酸が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、フェルラ酸は又はその塩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。
本発明において、「フェルラ酸の塩」とは、薬学的に許容される塩を意味する。フェルラ酸塩の塩形成用の塩基物質としては、例えば、アルカリ金属あるいはアルカリ土類金属の水酸化物、例えば、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、水酸化カルシウム、又は水酸化アンモニウムなどの無機塩基、アルギニン、リジン、ヒスチジン、オルニチンなどの塩基性アミノ酸、又はモノエタノールアミン、ジエタノールアミン、トリエタノールアミンなどの有機塩基が用いられるが、特に好ましいものとして、アルカリ金属あるいはアルカリ土類金属の水酸化物が挙げられる。
尚、フェルラ酸塩は、上記の塩を調製してから、その塩を医薬又は食品中に添加してもよいし、フェルラ酸と塩形成成分を医薬又は食品中に別々に添加して処方系中で塩を形成することでもよい。
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、フェルラ酸又はその塩を単独で、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、フェルラ酸又はその塩を単独で、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。当該食品中のフェルラ酸又はその塩の含有量(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>フェルラ酸は又はその塩を有効成分とするTRPV4活性抑制剤。
<2>フェルラ酸は又はその塩を有効成分とする過活動膀胱の予防又は改善剤。
<3>TRPV4活性抑制剤を製造するための、フェルラ酸は又はその塩の使用。
<4>過活動膀胱の予防又は改善剤を製造するための、フェルラ酸は又はその塩の使用。
<5>TRPV4活性抑制に使用するためのフェルラ酸は又はその塩。
<6>過活動膀胱の予防又は改善に使用するためのフェルラ酸は又はその塩。
<7>フェルラ酸は又はその塩を、それらを必要とする対象に有効量で投与又は摂取するTRPV4活性抑制方法。
<8>フェルラ酸は又はその塩を、それらを必要とする対象に有効量で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、フェルラ酸は30μMから300μMまで用量依存的にTRPV4活性を有意に阻害した。それに対して、フェルラ酸の類縁化合物である比較化合物1及び2に有意な阻害は認められなかった。
Claims (2)
- フェルラ酸は又はその塩を有効成分とするTRPV4活性抑制剤。
- フェルラ酸は又はその塩を有効成分とする過活動膀胱の予防又は改善剤。
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