JP5518489B2 - 頭部外傷誘導性の記憶障害および脳障害におけるブリオスタチン、ブリオログ、および他の関連物質の治療効果 - Google Patents
頭部外傷誘導性の記憶障害および脳障害におけるブリオスタチン、ブリオログ、および他の関連物質の治療効果 Download PDFInfo
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Description
本出願は、2007年2月9日出願の米国仮出願番号 60/900,339と2007年5月24日出願の米国仮出願番号60/924,662の優先権を主張し、これらの全体は引用することによりここに組み込まれる。
本願発明は、プロテインキナーゼC(PKC)を活性化する化合物または神経成長細胞(NGF)、脳由来神経栄養因子(BDNF)若しくは他の神経栄養因子を増強する化合物による頭部外傷の治療に関する。
頭部障害は、頭部に対する外傷であり、脳の障害を含んでいても、含んでいなくてもよい(脳障害についても参照されたい)。頭部障害の発生率(新患の数)は一年につき、100,000あたり300であり(人口の0.3%)、北米では100,00あたり25、英国では100,000あたり9の死亡数である。頭部外傷は、幼児期の入院の一般的な原因である。
PKCは、非受容体セリン-スレオニンプロテインキナーゼ最大の遺伝子ファミリーの一つとしてとして特定された。80年代初期におけるNishizukaとその共同研究者によるPKCの発見(Kikkawa et al. (1982) J. Biol. Chem. 257: 13341)、およびホルボールエステルのための主要な受容体としてのその特定(Ashendel et al. (1983) Cancer Res., 43: 4333)以来、多数の生理的シグナル伝達のメカニズムはこの酵素によるとされてきた。PKCへの強烈な関心は、カルシウム、およびジアシルグリセロール(およびそのホルボールエステル模倣剤)、即ち、その形成が成長および分化因子の作用によりリン脂質のターンオーバーと連結するエフェクター、によりインビトロで活性化される独特の能力に由来する。
ここで使用される場合、組成物の「投与」は、経口、皮下、腹腔内および筋肉内を含むいずれの投与経路も含む。
記憶及び学習障害の領域は、記憶及び学習過程の異なる特徴を論証することができる動物モデルにおいて豊富である。(必要であれば、例えば、Hollister, L.E., 1990, Pharmacopsychiat., 23, (Suppl II) 33-36を参照されたい)。記憶喪失や障害性の学習の利用可能な動物モデルは、離散的事象を記憶する動物の能力を測定することを伴う。これらの試験はモリス水迷路(Morris Water Maze)及び受動回避手順を含む。モリス水迷路において、動物は4つのクアドラント(quadrant) に分割されたタンク内において水泳させられ、そのうちの1つだけが水面下に安全なプラットフォームを有する。当該プラットフォームは取り除かれ、当該動物は間違ったクアドラントに対して正しいクアドラントを探すのにどのくらい時間がかかるかを試験される。受動回避手順において、当該動物は穏やかな電気衝撃が与えられる特有の環境を記憶し、2度目の時にはそれを回避する。受動回避手順の変形は、齧歯類が明るく開いた環境よりも暗く囲まれた環境を選択することを利用する。さらなる議論はCrawley, J. N., 1981, Pharmacol. Biochem. Behav., 15, 695-699; Costall, B. et al, 1987, Neuropharmacol., 26, 195-200; Costall, B. et al., 1989, Pharmacol. Biochem. Behav., 32, 777-785; Barnes, J.M. et al., 1989, Br. J. Pharmacol., 98 (Suppl) 693P; Barnes, J.M. et al., 1990, Pharmacol. Biochem. Behav., 35, 955-962において見つけることができる。
PKC 遺伝子ファミリーは現在、11遺伝子から成り、以下の4つのサブグループに分けられている:1) 典型的なPKCα, β1, β2(β1およびβ2は同じ遺伝子の選択的にスプライスされた形態である)およびγ、2) 新規なPKCδ, ε, ηおよびθ、3) 異型のPKCζ, λ, ηおよびi、ならびに4) PKCμ。PKCμは新規なPKCアイソフォームに類似するが、推定上の膜貫通ドメインを有することにより異なる(Blohe et al. (1994) Cancer Metast Rev. 13: 411; Ilug et al. (1993) Biochem J. 291: 329; Kikkawa et al. (1989) Ann. Rev. Biochem. 58: 31によって再検討された)。α, β1, β2およびγアイソフォームはCa 2+ 、リン脂質およびジアシルグリセロール依存であり、PKCの典型的なアイソフォームを代表し、一方、他のアイソフォームはリン脂質およびジアシルグリセロールによって活性化されるが、Ca2+には依存しない。すべてのアイソフォームは5つの可変(V1-V5)領域を包含し、α, βおよびγアイソフォームは高度に保存された4つの(C1-C4)構造ドメインを含む。PKCα, βおよびγ以外のすべてのアイソフォームはC2ドメインを欠き、当該λおよびηアイソフォームもまたジアシルグリセロールが結合するC1における2つのシステインリッチ亜鉛フィンガードメインの9個を欠く。C1ドメインはまた、すべてのアイソフォーム間で高度に保存された偽基質の配列を含み、これは当該酵素の不活性コンフォメーションを作り出すために、基質結合部位をブロックすることによって自己調節機能を果たす(House et al. (1987) Science 238, 1726)。
以下の実施例は本願発明をさらに説明するものであり、決してその範囲を限定するものとして解釈されてはならない。
微細外傷性脳障害(TBI)を30gマス (mass) を用いた震盪性のイベントによってマウスにおいて作製した。外傷後の1時間、マウスに腹腔内注射により1kgあたり20又は30μgのブリオスタチンを与えた。注射を合計5回の治療の間、週2回繰り返した。治療された動物でのブリオスタチン治療の学習及び記憶についての効果をモリス水迷路においてテストした。
モリス水迷路において、動物を4つのクアドラントに分割されたタンクの中で水泳させ、そのうち一つは安全なプラットフォームを水面下に有する。当該プラットフォームを取り除き、当該動物が間違ったクアドラントに対して正しいクアドラントを探すのにどのくらいの時間がかかったかを試験した。受動回避手順において、当該動物は穏やかな電気衝撃が伝わる特有の環境を記憶し、2度目の時にはそれを回避する。
微細外傷性脳障害 (TBI) をマウスにおいて、30 gマスを用いた震盪性のイベントにより作製した。外傷後1時間、マウスに腹腔内注射により1 kgあたり30μgのブリオスタチンを与えた。注射を、合計5回の治療の間、1週間あたり2回繰り返した。微細TBI後ブリオスタチンにより治療されたマウスのモリス水迷路における逃避潜伏期(escape latency)を、微細TBIの動物、TBIまたはブリオスタチンを受けていないコントロール動物、及びブリオスタチンのみ受けた動物と比較した。結果を図1に示す。
微細外傷性脳障害 (TBI) をマウスにおいて、30 gマスを用いた震盪性のイベントにより作製した。外傷後1時間、マウスに腹腔内注射により1 kgあたり20μgのブリオスタチンを与えた。注射を、合計5回の治療の間、1週間あたり2回繰り返した。微細TBI後ブリオスタチンにより治療されたマウスのモリス水迷路における逃避潜伏期を、微細TBIの動物、TBIまたはブリオスタチンを受けていないコントロール動物、及びブリオスタチンのみ受けた動物と比較した。結果を図2に示す。各治療群又はコントロール群の記憶保持を図3に表で示す。
以下に、本願出願の当初の特許請求の範囲に記載された発明を付記する。
(1) 頭部外傷を治療する方法であって、頭部外傷に罹患した患者を特定する工程と、プロテインキナーゼC(PKC)アクチベータ、4-メチルカテコール酢酸(MCBA)、または他のメチルカテコールの誘導体および薬学的に許容される担体を含む、頭部外傷の少なくとも一症状を治療するのに効果的な量の医薬組成物を前記患者に投与する工程とを含む方法。
(2) (1)に記載の方法であって、当該PKCアクチベータがFGF-18、大環状ラクトン、ベンゾラクタム、ピロリジノン、またはその組み合わせである方法。
(3) (2)に記載の方法であって、当該大環状ラクトンがブリオスタチンまたはネリスタチンである方法。
(4) (3)に記載の方法であって、当該ブリオスタチンがブリオスタチン-1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17または18である方法。
(5) (4)に記載の方法であって、当該ブリオスタチンはブリオスタチン-1である方法。
(6) (3)に記載の方法であって、当該ネリスタチンはネリスタチン-1である方法。
(7) (1)に記載の方法であって、当該医薬組成物は4-メチルカテコール酢酸を含む方法。
(8) (1)に記載の方法であって、前記投与は前記頭部外傷から1日以内に開始される方法。
(9) (1)に記載の方法であって、前記投与は前記頭部外傷から2日以内に開始される方法。
(10) (1)に記載の方法であって、前記投与は前記頭部外傷から3日以内に開始される方法。
(11) (1)に記載の方法であって、前記投与は前記頭部外傷の1〜2日目の間に開始される方法。
(12) (1)に記載の方法であって、前記投与は前記頭部外傷の1〜3日目の間に開始される方法。
(13) (1)に記載の方法であって、当該治療は1週間の期間継続する方法。
(14) (1)に記載の方法であって、当該治療は2週間の期間継続する方法。
(15) (1)に記載の方法であって、当該治療は3週間の期間継続する方法。
(16) (1)に記載の方法であって、当該治療は4週間の期間継続する方法。
(17) (1)に記載の方法であって、当該治療は6週間の期間継続する方法。
(18) (1)に記載の方法であって、前記治療は頭部外傷誘導性の脳障害を逆転させる方法。
(19) (1)に記載の方法であって、前記治療は頭部外傷誘導性の記憶障害を逆転させる方法。
Claims (5)
- 請求項1に記載の医薬組成物であって、当該医薬組成物の投与は前記頭部外傷の1〜3日目の間に開始される医薬組成物。
- 請求項1に記載の医薬組成物であって、当該医薬組成物による治療は1〜6週間の期間継続する医薬組成物。
- 請求項1に記載の医薬組成物であって、当該医薬組成物による治療は頭部外傷誘導性の脳障害または記憶障害を逆転させる医薬組成物。
- 請求項1に記載の医薬組成物であって、当該B環またはA環ブリオログが600から755の分子量および0.25nMから10μMのPKC親和性を有する医薬組成物。
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EP2754448A2 (en) | 2014-07-16 |
US20080207742A1 (en) | 2008-08-28 |
JP2014088406A (ja) | 2014-05-15 |
CA2873179A1 (en) | 2008-08-21 |
JP2010518091A (ja) | 2010-05-27 |
CN101848726A (zh) | 2010-09-29 |
EP3332797A2 (en) | 2018-06-13 |
CA2674773A1 (en) | 2008-08-21 |
EP2754448A3 (en) | 2014-12-24 |
JP2016128486A (ja) | 2016-07-14 |
US9974832B2 (en) | 2018-05-22 |
WO2008100449A3 (en) | 2009-05-22 |
WO2008100449A4 (en) | 2009-07-30 |
EP2121000A2 (en) | 2009-11-25 |
US20190083575A1 (en) | 2019-03-21 |
WO2008100449A2 (en) | 2008-08-21 |
EP3332797A3 (en) | 2018-08-01 |
EP2121000B1 (en) | 2015-09-23 |
KR20090119894A (ko) | 2009-11-20 |
ES2548766T3 (es) | 2015-10-20 |
JP6199176B2 (ja) | 2017-09-20 |
EP2959914A1 (en) | 2015-12-30 |
KR20140049054A (ko) | 2014-04-24 |
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