JP6226278B2 - 免疫細胞の活性化抑制剤およびその用途 - Google Patents
免疫細胞の活性化抑制剤およびその用途 Download PDFInfo
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- JP6226278B2 JP6226278B2 JP2014528240A JP2014528240A JP6226278B2 JP 6226278 B2 JP6226278 B2 JP 6226278B2 JP 2014528240 A JP2014528240 A JP 2014528240A JP 2014528240 A JP2014528240 A JP 2014528240A JP 6226278 B2 JP6226278 B2 JP 6226278B2
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Description
本発明の免疫細胞の活性化抑制剤は、前述のように、ブロムワレリル尿素またはその誘導体を含むことを特徴とする。
本発明の神経細胞の保護剤は、前述のように、本発明の免疫細胞の活性化抑制剤を含むことを特徴とする。本発明の神経細胞の保護剤は、例えば、神経細胞の変性抑制剤ということもできる。
本発明の神経疾患用医薬は、前述のように、本発明の免疫細胞の活性化抑制剤を含むことを特徴とする。
本発明の炎症性疾患用医薬は、前述のように、本発明の免疫細胞の活性化抑制剤を含むことを特徴とする。
本発明の免疫細胞の活性化抑制方法は、投与対象に、前記本発明の免疫細胞の活性化抑制剤を投与することを特徴とする。
本発明の神経細胞の保護方法は、投与対象に、前記本発明の神経細胞の保護剤を投与することを特徴とする。本発明の神経細胞の保護方法は、例えば、神経細胞の変性抑制方法ということもできる。
本発明の神経疾患の治療方法は、投与対象に、前記本発明の神経疾患用医薬を投与することを特徴とする。
本発明は、前記免疫細胞の活性化抑制のためのブロムワレリル尿素またはその誘導体であり、また、前記神経細胞の保護または変性抑制のためのブロムワレリル尿素もしくはその誘導体であり、また、前記神経疾患の治療のためのブロムワレリル尿素またはその誘導体であり、また、前記炎症性疾患の治療のためのブロムワレリル尿素またはその誘導体である。また、本発明は、前記各種医薬の製造のためのブロムワレリル尿素またはその誘導体の使用である。
ブロムワレリル尿素のパーキンソン病に対する効果を確認した。
以下に示すように、ブロムワレリル尿素およびLPS(リポポリサッカライド)の共存下、ラット新生仔由来一次培養マイクログリア(MG)を培養し、神経細胞傷害因子である一酸化窒素について、MGからの放出量を確認した。
前記(1)における一酸化窒素の放出抑制が、LPSで誘導される一酸化窒素合成酵素(誘導型;iNOS)の転写レベルの抑制であることを確認した。具体的には、前記(1)と同様にして、MG単独培養系について培養を行い、リアルタイム逆転写(RT)−PCRにより、iNOSのmRNAの転写量を測定した。リアルタイムRT−PCRは、常法にしたがって行った。そして、ブロムワレリル尿素が未添加の培養系のmRNAの転写量を100%として、各培養系について相対値(%)を求めた。
前記MGのみの培養系および前記MGと前記神経細胞の共培養系について、神経細胞特異的タンパク質であるMAP2の発現と一酸化窒素を産生するiNOSタンパク質の発現とを測定した。
6−ヒドロキシドーパミン(6−OHDA)でパーキンソン病を誘発するラットパーキンソン病モデルを使用し、ブロムワレリル尿素による神経細胞死の抑制を確認した。
相対値(%)=100×R/L
ブロムワレリル尿素の脳梗塞に対する効果を確認した。
右側中大脳動脈90分間一過性閉塞による脳梗塞モデルラットを使用し、ブロムワレリル尿素による組織喪失の抑制を確認した。
組織喪失の割合(%)=100×(L−R)/L
ブロムワレリル尿素による、脳梗塞巣に集積するマクロファージBINCsにおける前記iNOSの発現抑制および一酸化窒素の産生抑制を確認した。前記BINCsについては、Matsumotoら、Journal of Cerebral Blood Flow & Metabolism (2008) 28: 149-163を参照した。
ブロムワレリル尿素による、脳梗塞巣に集積するマクロファージBINCsにおける炎症性反応の抑制を確認した。
頭蓋外より注射針を刺入することによって脳損傷を起こすラット脳損傷モデルを使用し、ブロムワレリル尿素による組織喪失の抑制を確認した。
組織喪失の割合(%)=100×(L−R)/L
ブロムワレリル尿素の敗血症に対する効果を確認した。
Wistar雄8週齢ラット盲腸を結紮し、18ゲージ注射針によって結紮部盲腸に2箇所の穿孔を作成し、腹膜炎穿孔からのラット敗血症モデルとした。モデル作製の直後に、最終濃度500μg/mlとなるようにブロムワレリル尿素を溶解した、市販の維持輸液(ソリタT3、味の素製薬)10mlを、皮下に注射した。対照群は、ブロムワレリル尿素未添加の前記維持輸液のみを、同量、皮下に注射した。以後、約12時間ごとに、同様に注射をおこなった。また、開腹手術すなわち、皮膚と腹膜の切開を行っただけで、腸管に損傷を与えないラットを、偽手術群とした。前記偽手術群には、皮下注射は行わなかった。そして、切開から8日間にわたって、各群のモデルマットの結果を確認した。
ブロムワレリル尿素による、腹腔マクロファージによるインターロイキンの産生抑制を確認した。
敗血症モデルラットを使用し、ブロムワレリル尿素によるIL−6の抑制を確認した。
敗血症モデルラットを使用し、ブロムワレリル尿素による小腸の腫れと炎症の抑制を確認した。
ブロムワレリル尿素による、肺胞マクロファージによるiNOS誘導およびインターロイキン産生の抑制を確認した。
ブロムワレリル尿素による、炎症性皮膚疾患における炎症の抑制を確認した。
ヒルドイドソフト軟膏0.3%(マルホ株式会社製)に、1%(w/w)となるように、ブロムワレリル尿素を溶解し、ブロムワレリル尿素軟膏(BU軟膏)を調製した。次に、下着の着用時、前記下着のゴムにより生じた接触皮膚炎を原発巣とし、自家感作性皮膚炎に発展した炎症性皮膚疾患の患者に対して、腹部の丘疹を含む炎症領域(約25cm2)に、前記BU軟膏0.5gを塗布した。そして、前記BU軟膏の塗布直前、塗布後25分および3時間において、前記腹部を観察した。さらに、同患者に対して、引き続き、前記BU軟膏を1日2回、10日間、前記炎症領域に塗布した。そして、前記塗布開始から10日目の前記腹部および塗布を中止してから10日目(塗布開始から20日目)において、前記腹部を同様に観察した。
ストッキングの着用時、前記ストッキングのゴムにより両膝内側に接触皮膚炎を発症した患者に対して、左膝内側の線上の膨疹(約20cm2)に、前記(1)で調製したBU軟膏0.4gを塗布した。そして、前記BU軟膏の塗布直前および塗布後35分において、前記左膝内側を観察した。また、コントロールは、ブロムワレリル尿素未添加の前記ヒルドイドソフト軟膏0.3%(コントロール軟膏)を使用し、同患者の右膝内側の線上の膨疹に塗布した以外は、同様にして前記右膝内側を観察した。
マウスアトピー性皮膚炎モデルマウスを使用し、ブロムワレリル尿素によるアトピー性皮膚炎における炎症の抑制を確認した。
Claims (8)
- 免疫細胞の活性化抑制剤であり、
前記免疫細胞は、マイクログリアまたはマクロファージであり、
ブロムワレリル尿素またはその異性体もしくは塩、またはそれらの溶媒和物もしくは水和物を含むことを特徴とする免疫細胞の活性化抑制剤(ただし、ロキソプロフェンを含む免疫細胞の活性化抑制剤を除く)。 - ブロムワレリル尿素またはその異性体もしくは塩、またはそれらの溶媒和物もしくは水和物を含むことを特徴とする神経細胞の保護剤(ただし、ロキソプロフェンを含む神経細胞の保護剤を除く)。
- ブロムワレリル尿素またはその異性体もしくは塩、またはそれらの溶媒和物もしくは水和物を含むことを特徴とする神経疾患用医薬(ただし、ロキソプロフェンを含む神経疾患用医薬を除く)。
- 前記神経疾患が、パーキンソン病およびアルツハイマー病の少なくとも一方の変性神経疾患である、請求項3記載の神経疾患用医薬。
- 前記神経疾患が、脳梗塞および脳損傷の少なくとも一方の急性神経疾患である、請求項3記載の神経疾患用医薬。
- 炎症性疾患用医薬であり、
前記炎症性疾患は、全身性炎症反応症候群または炎症性皮膚疾患であり、
ブロムワレリル尿素またはその異性体もしくは塩、またはそれらの溶媒和物もしくは水和物を含むことを特徴とする炎症性疾患用医薬(ただし、ロキソプロフェンを含む炎症性疾患用医薬を除く)。 - 前記全身性炎症反応症候群が、敗血症である、請求項6記載の炎症性疾患用医薬。
- 前記炎症性皮膚疾患が、アトピー性皮膚炎、接触皮膚炎、乾癬、湿疹、おむつ皮膚炎、脂漏性皮膚炎、ヴィダール苔癬、自家感作性皮膚炎、老人性乾皮症、光線性皮膚疾患、水疱症、ケロイド、紅皮症、薬疹および中毒疹からなる群から選択された少なくとも一つである、請求項6記載の炎症性疾患用医薬。
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