JP2016523866A - 慢性外傷性脳障害iを予防及び/又は治療する方法 - Google Patents
慢性外傷性脳障害iを予防及び/又は治療する方法 Download PDFInfo
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Abstract
Description
現在、多数の臨床研究及び実験的研究が、震盪性損傷後に、過剰リン酸化されたタウの蓄積が存在することを示している。過剰リン酸化されたタウを含有する神経原線維濃縮体の蓄積は、特に、この蓄積を、表面の新皮質層内、詳細には、溝の基底部にて血管周囲かつ優勢に見出すとき、慢性外傷性脳障害の特徴的病理である。ヒト研究(McKeeら、2009、J Neuropath Exp Neurol 68、709〜735)において、例えば、過剰リン酸化されたタウのかかる分布は、繰り返された震盪事故の既往歴を有する対象において容易に明らかである(図1)。この特定の実施例において、過剰リン酸化されたタウの局在性を、繰り返された震盪の既往歴を有するNFLフットボールプレーヤーにおいて示す。溝の基底部にて、最大の蓄積を有する過剰リン酸化されたタウの血管周囲局在性(A)に注意されたい。この病理は、慢性外傷性脳障害に固有である。今日までのこれらの研究において用いた実験動物における溝の非存在が、かかる蓄積が、溝の基底部での局在性のヒトパターンを再現するという証明を不可能にしたが、過剰リン酸化されたタウの類似の蓄積を、動物における実験的震盪後に示した。
本発明者らは、過剰リン酸化されたタウが、震盪性損傷後に血管周囲に蓄積するということを確立し、震盪が、サブスタンスPの血管周囲での放出を生じるかどうかを調査するための震盪動物モデルを用いた。本発明者らは、震盪事故を再現するために震盪のげっ歯類モデルを開発し(Donkinら、2004、7th International Neurotrauma Symposium、75〜78ページ、Medimond Publishers、Bologna、Italy)、かかる事故後にサブスタンスPを放出したかどうかをその後に決定した。震盪事故後の脳血管周囲でのサブスタンスP免疫活性における明確な増大が存在する(図2)。本発明者らは、感覚神経線維の機械的刺激が、サブスタンスPのこの血管周囲での放出に関与したことを提案する。これらの結果は、感覚神経線維の機械的刺激が、サブスタンスP放出を誘導することを示す、非脳組織における従前の研究と一致する(Angら、2011、PLoS One 6、e24535)。
本発明者らは、機械的損傷が、震盪性損傷後にサブスタンスPの放出を生じることを示し、次に、サブスタンスPNK1受容体アンタゴニストが、震盪性損傷後にタウ過剰リン酸化を低減するかどうかを調査した。図3は、震盪性損傷後のタウリン酸化に対するNK1受容体アンタゴニスト(n−アセチル−L−トリプトファン)の作用を示す。ラットにおける震盪性損傷が、損傷していない動物(A、B)と比較して、震盪事故の3日後に広範なタウリン酸化(C、D)を生じることに注意されたい。損傷誘導の30分後でのNK1受容体アンタゴニストの投与は、この3日の時間点でのタウリン酸化のほぼ完全な阻害をもたらす(E、F)。故に、NK1受容体アンタゴニストの投与は、タウ過剰リン酸化を予防し、故に、CTEの発症を予防する。
本発明者らは、サブスタンスPアンタゴニストが、震盪性損傷後にタウ過剰リン酸化を阻害することを確立し、阻害が生じる機序は、サブスタンスPのそのNK1受容体への結合、並びにタウの過剰リン酸化、及び慢性外傷性脳障害(CTE)の発症を生じる種々の生化学的酵素(キナーゼ)の活性化を通じてであることを提案する。この活性化の機序を、図4において示す。震盪性損傷中の機械的受容器の活性化は、サブスタンスPの放出を生じる(実施例2、及びAngら、2011、PLoS One 6、e24535)。さらに、サブスタンスP放出及びその受容体の活性化の程度は、刺激の頻度に比例する(Mantyh、2002、J.Clin.Psychiatry 63、6〜10)。具体的には、SPを放出する機械的刺激、例えば、震盪への繰り返された暴露は、サブスタンスP受容体の発現を長期間(>8日)増大し、隣接するサブスタンスP受容体を発現するニューロンのより強力な活性化を導く。さらに、繰り返された刺激は、より多くのサブスタンスP放出を導き、サブスタンスPの放出の血管周囲部位からのより多くの拡散、及びより遠位のニューロンの刺激をもたらす。約3〜5倍多くのニューロンが、より頻繁な刺激に応答して活性化されることを確立した(Mantyh、2002、J.Clin.Psychiatry 63、6〜10)。本発明者らが実施例3において示す通り、サブスタンスP受容体アンタゴニストの投与は、サブスタンスP受容体の活性化を予防し、タウ過剰リン酸化に関与する酵素の活性化を予防し、故に、かかるタウ過剰リン酸化、及び慢性外傷性脳障害の発症/進行を予防する。
両方の、サブスタンスPの放出と、過剰リン酸化されたタウの蓄積が、震盪事故後に生じたことを確立し、なぜ、ヒトCTEにおける過剰リン酸化されたタウの蓄積が、脳溝の基底部にて顕著であったかを示すことが残っている。本発明者らは、サブスタンスP放出が、感覚神経線維において機械的受容器の刺激に応答して生じることを、実施例2において示した。現在の開示における1つの高度に革新的なステップは、ヒトを含む、皺脳の動物において、溝が、圧力点を溝の基底部に集中させることにより、大脳皮質を機械的損傷から保護するという認識である。これは、両方の、溝を脳組織内部に取り込み、溝を脳組織内部から排除し、機械的圧力の作用をその後刺激する脳組織モデルにおいて最も説明される(Clootsら、2008、Ann.Biomed.Eng.36、1203〜1215)。溝あり及びなしの脳組織を再現したモデルにおける回転加速である代表的な機械的圧力の作用の刺激を、図5において示す。より高い機械的圧力を黒色として示す。これらの結果は、モデルへの溝の付加が、溝の形態論に関係なく、圧力を溝の基底部に集中させることを明確に示す。この機械的圧力パターンは、CTEにおいて報告し、図1において示した過剰リン酸化されたタウの検死後の局在性と顕著に類似する。
Claims (15)
- 対象に有効量のサブスタンスP受容体アンタゴニストを投与するステップを含む、慢性外傷性脳障害を予防及び/又は治療する方法。
- 疾患、状態又は容態が、慢性外傷性脳障害と関連するタウ過剰リン酸化に起因する、請求項1に記載の方法。
- サブスタンスP受容体アンタゴニストが、NK1受容体アンタゴニスト、NK2受容体アンタゴニスト、又はNK3受容体アンタゴニストである、請求項1又は2に記載の方法。
- 前記NK1受容体アンタゴニストが、カソピタント、CGP49823、CP−122,721、CP−96,345、CP−99,994、FK888、GR82334、GR94800、GR203040、GR−205171、GSK1144814、GSK206136、GSK424887、GW679769、HSP−117、L703,606、L732,138、L733,060、L742,694、L668,169、LY303241、LY303870、LY306740、マロピタント、MEN11149、オルブピタント、PD154075、R−544、RP−67580、RPR100893、SCH619734、スパンタイドII、スパンタイドIII、スペンジド、SR140333、ベスチピタント、WIN−41,708、WIN−62,577、又はその誘導体、変異体、類似体、薬学的に許容される塩、互変異性体若しくはプロドラッグからなる群の1つ又は複数から選択される、請求項3に記載の方法。
- NK2受容体アンタゴニストが、SR−48968、L−659877、GR103537、MGN−10627、SR144190及びGR94800、又はその誘導体、変異体、類似体、薬学的に許容される塩、互変異性体若しくはプロドラッグからなる群の1つ又は複数から選択される、請求項3に記載の方法。
- NK3受容体アンタゴニストが、SR−143,801、R820、R486、SB222200、L758,298及びNKP608、又はその誘導体、変異体、類似体、薬学的に許容される塩、互変異性体若しくはプロドラッグからなる群の1つ又は複数から選択される、請求項3に記載の方法。
- サブスタンスP受容体アンタゴニストが、対象に0.25mg/kg〜25mg/kgの用量で投与される、請求項1〜6のいずれか一項に記載の方法。
- 慢性外傷性脳障害と関連する疾患、状態又は容態の進行を低減する、請求項1〜7のいずれか一項に記載の方法。
- 慢性外傷性脳障害と関連する疾患、状態又は容態を予防及び/又は治療するための医薬の製造におけるサブスタンスP受容体アンタゴニストの使用。
- サブスタンスP受容体アンタゴニストを含む、慢性外傷性脳障害と関連する疾患、状態又は容態を予防及び/又は治療するために用いられる医薬組成物。
- サブスタンスP受容体アンタゴニストが、NK1受容体アンタゴニスト、NK2受容体アンタゴニスト、又はNK3受容体アンタゴニストである、請求項10に記載の医薬組成物。
- NK1受容体アンタゴニストが、カソピタント、CGP49823、CP−122,721、CP−96,345、CP−99,994、FK888、GR82334、GR94800、GR203040、GR−205171、GSK1144814、GSK206136、GSK424887、GW679769、HSP−117、L703,606、L732,138、L733,060、L742,694、L668,169、LY303241、LY303870、LY306740、マロピタント、MEN11149、オルブピタント、PD154075、R−544、RP−67580、RPR100893、SCH619734、スパンタイドII、スパンタイドIII、スペンジド、SR140333、ベスチピタント、WIN−41,708、WIN−62,577、又はその誘導体、変異体、類似体、薬学的に許容される塩、互変異性体若しくはプロドラッグからなる群の1つ又は複数から選択される、請求項11に記載の医薬組成物。
- NK2受容体アンタゴニストが、SR−48968、L−659877、GR103537、MGN−10627、SR144190及びGR94800、又はその誘導体、変異体、類似体、薬学的に許容される塩、互変異性体若しくはプロドラッグからなる群の1つ又は複数から選択される、請求項11に記載の医薬組成物。
- NK3受容体アンタゴニストが、SR−143,801、R820、R486、SB222200、L758,298及びNKP608、又はその誘導体、変異体、類似体、薬学的に許容される塩、互変異性体若しくはプロドラッグからなる群の1つ又は複数から選択される、請求項11に記載の医薬組成物。
- i)慢性外傷性脳障害と関連する疾患、状態又は容態を予防及び/又は治療すること、
ii)慢性外傷性脳障害と関連する疾患、状態又は容態の進行を阻害すること
のいずれか又は両方のために用いられる、請求項9〜14のいずれか一項に記載の医薬組成物。
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