JP2008534515A - プロゲステロンの漸減投与を介した中枢神経系損傷の治療の方法 - Google Patents
プロゲステロンの漸減投与を介した中枢神経系損傷の治療の方法 Download PDFInfo
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- JP2008534515A JP2008534515A JP2008503262A JP2008503262A JP2008534515A JP 2008534515 A JP2008534515 A JP 2008534515A JP 2008503262 A JP2008503262 A JP 2008503262A JP 2008503262 A JP2008503262 A JP 2008503262A JP 2008534515 A JP2008534515 A JP 2008534515A
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Abstract
Description
本発明は、the National Institute of Healthのthe National Institute of Neurological Disorders and Stroke(NINDS)によって与えられた助成金番号R01 N5038664−04およびR01 N5040825−03の下の米国政府支援によって行われた。米国政府は、本発明において一定の権利を有する。
本発明は、中枢神経系に対する外傷性または虚血性の傷害を治療する方法に関する。
プロゲステロン、その代謝産物、およびその他の性腺ステロイド、例えばエストロゲンおよび場合によってはテストステロンが有効な神経保護薬であるとの実験的証拠が増えてきているが、これらのホルモンが中枢神経系に作用して修復を促す具体的な生理学的機序は完全には理解されていない。また、プロゲステロンは、性腺ホルモンであるだけでなく、神経ステロイドと呼ばれるオートクリン/パラクリンホルモンのファミリーにも属している。神経ステロイドは、内分泌源とは無関係に脳に蓄積し、グリア細胞にあるステロール前駆体から合成することができるステロイドである。これらの神経ステロイドは、GABA伝達を促進し、グルタミン酸塩の作用を調節し、ミエリンの産生を促進し、炎症性サイトカインの発現を低下させ、また、活性化ミクログリアからフリーラジカルが放出されるのを防止することができる。
Roofら(1994)Experimental Neurology 129:64−69 Jiangら(1996)Brain Research 735:101−107 Baulieu,E.E.(1992)Adv.Biochem.Psychopharmacol.47:1−16 Robelら(1995)Crit.Rev.Neurobiol.9:383−94 Lambertら(1995)Trends Pharmacol.Sd.16:295−303 Baulieu,E.E.(1997)Recent Prog.Horm.Res.52:1−32 Reddyら(1996)Psychopharmacology 128:280−92 Mauriceら(1998)Neuroscience 83:413−28 Mauriceら(1996)J.Neurosci.Res.46:734−43 Reddyら(1998)Neuroreport 9:3069−73 Lyethら(1992)J Neurotrauma 9(2):S463−74 Hayesら(1992)J Neurotrauma 9(1):S173−87
CNSにおけるニューロン損傷を治療または予防する方法が提供される。特に、本発明は、CNSへの外傷性または虚血性の傷害の後、治療上有効な量のプロゲスチンまたはプロゲスチン代謝産物を、退薬を回避するために、プロゲスチンまたはプロゲスチン代謝産物の投与を停止する前に漸減するように投与する方法を提供する。使用される薬剤漸減法は、線形漸減法、指数的漸減法、投薬する用量を50%ずつに徐々に減らしていく方法などを含むことができ、または、治療に対する患者の応答を治療に当たっている医師の評価に基づいて決定することも可能である。本発明の漸減投与法は、外傷性または虚血性のCNS傷害を治療するために、治療上有効な量のプロゲスチンまたはプロゲスチン代謝産物を投与するための如何なる治療用プロトコールまたはレジメンとも併用することができる。
本発明は、中枢神経系に対する外傷または虚血性傷害の後に起こる神経変性を治療または予防する方法および組成物を提供する。具体的には、本発明の方法は、CNSに外傷または虚血性傷害が起きた後に、治療上有効な量のプロゲスチンまたはプロゲスチン代謝産物を投与し、退薬を回避するために、プロゲスチンまたはプロゲスチン代謝産物の投与を停止する前にその投与を漸減するように投与することを提供する。本明細書の他の箇所でさらに詳細に説明しているように、本発明は、漸減投与が、プロゲスチンまたはプロゲスチン代謝産物の投与を突然中止する場合よりもより有利なCNS修復が可能であることを実証する。
方法:
雄のスプレイグ−ドーリー(Sprague−Dawley)ラット(300g)を飼育かごの中で個別に飼育し、逆転させた明暗周期(0800〜2000時)に置いた。動物を以下の4つの群の一つに割り当てた:(1)傷害(n=7)、(2)傷害+3日間のプロゲステロン処理(LP3;n=7)、(3)傷害+5日間のプロゲステロン処理(LP5;n=7)、および(4)模擬処理(n=8)。動物に対する処理はすべて、実験動物の管理と使用に関する指針(the Guide for the Care and Use of Laboratory Animals)(U.S.Department of Health and Human Services,Pub no.85−23,1985)に示されたガイドラインに従って行い、エモリー大学実験動物管理使用委員会(the Emory University Institutional Animal Care and Use Committee)による承認を受けた。
組織学:ほとんどの動物において、壊死組織は主に内側前頭前野および帯状皮質に限定されていた。しかし、場合によっては、より重篤な組織損傷が、脳梁、ならびに内側中隔および内側線条体の背側面の大部分の内部に広がっていた(データ省略)。壊死空洞形成に対する顕著な主効果が3つの傷害群の間で観察された(F2,19=3.57、P<.05)。テューキー事後分析により、壊死空洞形成が用量に依存して減少することが明らかになった。データ省略。とりわけ、プロゲステロンを投与された動物はすべて、ビヒクルを注射された傷害動物と比較して傷害が小さくなる傾向にあった。しかし、わずか5日間のプロゲステロンによって、壊死空洞形成全体が顕著に減少した(P<.05)。また、本発明者らは、対照動物と比較して、すべての傷害群において側脳室が拡大することを観察した(F3,25=5.28、P<.01)が、プロゲステロンはこの測定結果にまったく影響を及ぼさなかった。データ省略。平均線条体面積の測定値について、群間差異は見られなかった。
傷害によって誘発される壊死空洞形成が減少したことは、傷害後の神経ステロイドによる介入が、この動物モデルにおいて、TBI後の傷害量を減少させ得ることの証拠となる。本実験において、本発明者らは、プロゲステロン処理された動物において、壊死空洞形成が用量に依存して減少することを観察した。特に、3日間だけしかプロゲステロンで処理されなかった動物(LP3)の脳の壊死空洞は、傷害動物の脳のものよりも小さくなる傾向があったが、わずか5日間の処理措置(LP5)により、著しく小さい傷害となった。ここで、本発明者らの研究は、プロゲステロンもTBIに誘発される実質損失を減弱することができるということの第一の証拠を提供する。
実施例2:シクロデキストリンビヒクルに入れたプロゲステロンの投与に対する、TBI後の行動の回復の用量応答曲線
方法:
実施例1に概略したように、外傷性脳傷害を誘発するために手術を行った。実施例1に概略したように、モーリス水迷路を使用する行動試験を実施し、巧妙な接着物はがし(tactical adhesive removal)についての方法を実施した。
結果:
図1Aおよび1Bは、低用量および中用量のプロゲステロン(シクロデキストリン含有ビヒクル中8mg/kgおよび16mg/kg)では、モーリス水迷路の成績が一貫して向上を示したが、一方、高用量のプロゲステロン(シクロデキストリン含有ビヒクル中32mg/kg)では有益な効果が見られなかった。
実施例3:漸減的プロゲステロン退薬は外傷性脳傷害後の回復を促進させる
方法:
雄スプレイグ−ドーリーラットに、前頭前野中央部の傷害または模擬手術を施した。傷害後1時間目および6時間目、ならびに7日の間24時間ごとに注射を施した。処理群(n=8)は、傷害を受けた(I)および模擬処理(S)の急激な退薬(AW)、漸減的な退薬(TW)ならびにビヒクル(V)処理を包含していた。TW注射を、最後の2回の処理まで次第に半減させていった。手術後、退薬中および退薬後に行動実験を実施した。行動実験箱を使用して、上下運動および探索行動を調べた。また、感覚無視および不安行動も解析した。傷害後8日目または3週目に、脳採取を行った。潅流組織切片を、傷害量および免疫組織化学的応答に関して解析した。新鮮な脳組織は、冷却2−メチルブタンで急速冷凍してからウエスタンブロット解析のためにホモジナイズした。
結果:
急激な退薬と傷害(AWI)とは相互作用して、漸減的なプロゲステロン退薬(TWI)と較べると、不安、運動障害および感覚障害を増大させる。さらに、急激な退薬−模擬処理(AWS)ラットでは、他のすべての模擬ラットと比較して、運動不全が増大し、プロゲステロン漸減ラットと比較して不安を増大させた。神経保護因子BDNFおよびHSP70が、傷害後3週間で、TWI、AWI、VIの順に増加した。漸減ホルモン治療法のこの優れた効果は、傷害の復元(reconstruction)およびGFAP染色と相関した。すなわち、TWI動物の傷害容量が最も少なく、反応性星状細胞の数も最も少なく、次いてAWIで少なかったが、一方、VIの傷害容量が最も多く、また反応性星状細胞の数も最も多かった。アポトーシスおよび炎症は、p53、活性型カスパーゼ3、TNFα、およびNFκβによって示された通り、TWで低下した。
結論
急激なPWは、外傷性脳傷害後の行動回復および組織回復に対して強力な効果をもつ。退薬のピーク時に、プロゲステロン退薬症候群を起こしている動物は、不安、感覚障害、および運動障害の増大を示すが、これらは全て、傷害によってさらに悪化する。一週間後、AWI動物においては、行動障害の増大がなお顕著である。ウエスタンブロットにより、漸減的な退薬によって、アポトーシスおよび炎症に関連するタンパク質の発現が減少することが明らかになったが、すべてのプロゲステロン処理が、ビヒクルのみの対照よりも優れた転帰をもたらした。傷害後3週目で、傷害および急激なプロゲステロン退薬の複合効果は、プロゲステロン処理を徐々に減らした動物よりも大きな行動障害をもたらし続けた。これらの発見は、臨床試験において、投薬計画の最後に処理を突然停止するよりも、プロゲステロンを漸減的に退薬させた方が、CNS修復に有益であることを示唆するものと考えられ得る。
実施例4:プロゲステロンの漸減的退薬は、外傷性脳傷害後の長期にわたる回復を促進する。
材料および方法:
被験体。傷害時に体重290〜310gの雄のスプレイグ−ドーリーラット60匹を本実験で使用した。手術の前後に食餌と水とは自由摂取させた。手術の7日前に到着してから、手術後3週目に脳を切除するまで、毎日動物の世話をし、体重を測定した。動物は、各実験条件につきn=10とし、12の小集団に分けて世話をした。動物の処理はすべて、エモリー大学実験動物管理使用委員会のプロトコール第131−2002号による承認を受けた。
結果:
行動アッセイ。
考察
本実験では、傷害後3週間の急激なプロゲステロン退薬の効果を調べ、選択的な長期にわたる影響があることを発見した。長期にわたる行動学的、解剖学的、および分子的な機能のいくつかの目安を調べて、活動、感覚、および細胞応答の回復を示した。
まとめ
成獣の雄スプレイグ−ドーリーラットに、両側性前頭皮質挫傷(L)手術または模擬(S)手術を行った。傷害後1時間目および6時間目、その後24時間おきに6日間、ラットに注射を行った。ビヒクル(V)処理したラットに22.5%シクロデキストリンを9回注射したが、AWラットには、16mg/kgのプロゲステロンを9回注射し、TWラットには、16mg/kgのプロゲステロンを7回注射した後、8mg/kgを1回、また4mg/kgを1回注射した。8日目に、感覚無視試験と自発運動試験とを開始した。TBI後22日目に動物を殺して、分子的解析または組織学的解析のために脳を調製した。ウエスタンブロッティングによって、TW動物対AW動物においてBDNFおよびHSP70が増加することが明らかになった。P53はVL動物で増加したが、プロゲステロン処理群はすべて、模擬処理群と同等であった。TW動物は、AW動物よりも感覚無視が顕著に低下し、自発運動アッセイ法ではセンター部分滞在時間が増加した。さらに、傷害の復元によって、AWL動物よりもTWL動物、VL動物よりもAWL動物で傷害サイズが減少したことを明らかにした。GFAP免疫蛍光染色も、このパターンをたどる。結論として、TBIの後、AWは、慢性回復期間における選択された行動および分子マーカーに影響を与える。
Claims (10)
- 治療上有効量のプロゲステロンを、それを必要とする被験体に投与することを含む、中枢神経系の外傷性傷害を治療する方法であって、プロゲステロンの投与を停止する前に、該投与が漸減投与投薬レジメンを含む方法。
- 中枢神経系の前記外傷性傷害が外傷性脳傷害である、請求項1に記載の方法。
- 前記外傷性脳傷害が鈍器による挫傷によって生じる、請求項2に記載の方法。
- 前記漸減投与投薬レジメンが、プロゲステロンの投薬量を50%ずつ徐々に減らしていくことを含む、請求項1に記載の方法。
- 前記漸減投与投薬レジメンが線形の漸減を含む、請求項1に記載の方法。
- 前記線形の漸減が10%の線形漸減である、請求項5に記載の方法。
- 前記漸減投与投薬レジメンが指数漸減を含む、請求項1に記載の方法。
- 前記漸減投与投薬レジメンを、プロゲステロンを一日に少なくとも一回投与することと併用して用いる、請求項1に記載の方法。
- 前記漸減投与投薬レジメンの前に前記被験体に投与される前記治療上有効量のプロゲステロンが、プロゲステロンの一定量投薬レジメンを含む、請求項1に記載の方法。
- 前記漸減投与投薬レジメンの前に前記被験体に投与される前記治療上有効量のプロゲステロンが、プロゲステロンの二段階投薬レジメンを含む、請求項1に記載の方法。
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