JP2009149677A - プロラクチン誘導性の神経幹細胞数の増加ならびにその治療用途 - Google Patents
プロラクチン誘導性の神経幹細胞数の増加ならびにその治療用途 Download PDFInfo
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- JP2009149677A JP2009149677A JP2009043519A JP2009043519A JP2009149677A JP 2009149677 A JP2009149677 A JP 2009149677A JP 2009043519 A JP2009043519 A JP 2009043519A JP 2009043519 A JP2009043519 A JP 2009043519A JP 2009149677 A JP2009149677 A JP 2009149677A
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Abstract
【解決手段】ポリペプチドホルモンであるプロラクチンを用いることによって、神経幹細胞の数または神経新生を増加させる方法および医薬。この方法は、インサイチュでより多くの神経幹細胞を得るためにインビボで実行され得、欠損または機能不全の神経細胞を補償するためにより多くのニューロンまたはグリア細胞を、順次産生し得る。この方法はまた、培養において多くの神経幹細胞を産生するためにインビトロで実施され得る。この培養された幹細胞は、例えば、神経変性疾患または神経変性状態に罹患した患者または動物の移植処置のために使用され得る。また、プロラクチンを含有する医薬を投与することによっても神経幹細胞の数を増加させ得る。該神経変性疾患としては、特にアルツハイマー病、多発性硬化症、ハンティングトン病、筋萎縮性側索硬化症、およびパーキンソン病である。
【選択図】図1
Description
本発明は、プロラクチンを使用することによって神経幹細胞数を増加させる方法を提供する。この方法は、インサイチュでより多くの神経幹細胞を得るためにインビボで実施され得、これは、欠損した神経系細胞または機能不全の神経系細胞を補償するためにより多くのニューロンまたはグリア細胞を産生し得る。この方法はまた、培地における多くの神経幹細胞を産生するためにインビトロで実施され得る。この培養された幹細胞は、例えば、神経変性疾患または神経変性状態に罹患しているか、あるいは神経変性疾患または神経変性状態を有すると疑われる患者または動物の移植処置のために、使用され得る。
「神経幹細胞」は、神経系の細胞系統における幹細胞である。幹細胞は、自己複製し得る細胞である。言い換えると、幹細胞の分割から生じた娘細胞は幹細胞を含む。神経幹細胞は、神経系の細胞系統における全ての細胞型(ニューロン、アストロサイトおよびオリゴデンドロサイト(アストロサイトおよびオリゴデンドロサイトはまとめて、グリアまたはグリア細胞と呼ばれる)を含む)に最終的に分化し得る。従って、本明細書中で言及される神経幹細胞は、多能性の神経幹細胞である。
脳に及ぼす妊娠関連ホルモン/生理学的変化の影響を評価する試みにおいて、本発明者らは、神経幹細胞の数(NSC)が妊娠の間二波パターンで増加することを発見した。従って、妊娠7日目で検出可能な様式でNSC数が増加し、妊娠14日目で最大40%の増加に達し、生誕の際にベースラインに戻った。驚くべきことに、生誕後、分娩後の最初の1週間の間に、第2の増加が起こった。神経幹細胞が主に位置する脳室下帯における増殖細胞の数がまた、妊娠の間、二波パターンで増加し;妊娠7日後に倍になり、妊娠14日後にベースラインに戻り、そして生誕時に第2の増加が続いた(実施例1)。
本発明は、プロラクチンと少なくとも1つのさらなる因子とを含む組成物を提供する。このさらなる因子は、神経幹細胞数を増加させ得るか、またはニューロンもしくはグリア細胞への神経幹細胞の分化を増強し得る。このさらなる因子は、好ましくは、エリスロポエチン、EGFおよび/またはPACAPである。
(神経幹細胞の培養)
神経幹細胞の培養のためのプロトコールは、米国特許第5,750,376号またはShingoら,2001に詳細に記載される。簡単にいうと、胚性神経幹細胞を、E14内側神経節隆起および側方神経節隆起から調製した。成体の神経幹細胞を、成体マウスの脳室下帯から調製した。組織を、20ng/ml EGF、または各々の場合に示されるような他の増殖因子を含む基本培地内で培養して、ニューロスフィア(neurosphere)を形成した。基本培地の組成は、以下の通りである:DMEM/F12(1:1);グルコース(0.6%);グルタミン(2mM);炭酸水素ナトリウム(3mM);HEPES(5mM);インスリン(25μg/ml);トランスフェリン(100μg/ml);プロゲステロン(20nM);プトレシン(60μM);および塩化セレン(30nM)。
成体雄性Long−Evansラット(250〜350g)を、Charles River Breeding Farms(Laval,Quebec,Canada)から入手し、すべての処理前に、2週間にわたってコロニーに適合させた。手術の1週間前に、このラットに、前脚抑止試験におけるベースライン試験を行った。
脳卒中研究のための動物に、感覚運動皮質の片側脈管遮断を施した。イソフルラン麻酔を用いて、皮膚を切開し、収縮させ、そして表面に存在する筋膜を頭蓋から取り除いた。頭蓋の開口部を、硬膜を傷つけないように注意しながら、以下の座標に作製した:AP +4.0〜−2.0;L 1.5〜4(傍矢状の隆線;Kolbら,1997)。この硬膜を切り、頭蓋の開口部から収縮させた。滅菌生理食塩水中に浸漬した綿棒で、露出した軟膜越しに穏やかに擦り、血管を除いた。次いで、反対側の半球に穴を開け、浸透圧ミニポンプを備えたカニューレのための開口部を、AP −0.5;L 1.5に提供した。浸透圧ミニポンプを、肩甲骨の間の皮膚の下に配置し、そしてチューブを、速乾性セメントで頭蓋に付けたカニューレに皮膚の下で接続した。一旦止血が達成されると、頭皮を5−O 滅菌縫合糸を用いて縫合して閉じた。この動物に、Banamine(鎮痛薬)の注射を1回与え、そしてそのホームケージに戻した。骨に穴を開けた偽性動物には麻酔のみを与え、そして皮膚を切開し、そして縫合した。
この試験は、新皮質前方領域の機能的な保全性に関して、感度の高い測定を構成することが示されている。正常なラットにおいて、泳ぎは、後肢からの推進力によって達成される。前肢は、通常、任意の動作が抑止され、動かずに、そしてその動物の頚部の下部と一緒になったままである。前肢の抑止は、泳いでいる間、動物を撮影することによって評価された。動物を、室温の水(約25℃)で深さ25cmまで満たした水槽(30w × 90l × 43h cm)の一方の端に導入し、これらの動物が、9.5cm四方の可視的プラットフォームに泳ぐのを撮影した。このプラットフォームを、水面の2cm上に張り出させ、そして水槽の反対側の端に配置する。水槽の長さに沿った3回の泳ぎにおいて、各前肢によってなされることがある場合、動作回数の計数によって抑止のスコアリングを行った。泳ぎは、動物が、泳ぎを試行している間に水槽の側面に接触しなかった場合にのみ、スコアリング可能であるとみなした。
6週目の終りに、動物に過剰用量のエタノール(Euthanol)を与え、そしてピクリン酸中にある0.9%生理食塩水および4%パラホルムアルデヒドで心臓内を灌流した。この脳を凍結保護し、そしてビブラトームで、40ミクロンに切った。5セットの切片を、400ミクロンごとにした。2セットを染色した(一方をクレシルバイオレットで、そしてもう一方をダブルコルチンで)。残りのセットは、保存した。クレシルバイオレット染色を、スライド上で実施し、一方ダブルコルチンは、自由に浮遊する切片における免疫組織化学手順として実施した。クレシルバイオレット染色は、損傷範囲の評価を可能にし、一方、ダブルコルチンは、移動性の神経前駆細胞中に存在する微小管結合タンパク質を染色する。
成体CD1マウスの前脳における神経幹細胞数を、妊娠マウス(6〜8週齢)および週齢の一致した処女マウスにおいて決定し、妊娠の影響を研究した。成体雌性マウスの前脳(両方の半球)の脳室下帯全体を、妊娠の間の種々の時点で収集し、切開し、酵素的に解離し、そして米国特許第5,750,376号に記載されているように、上皮増殖因子の存在下において、規定された培養培地中にプレーティングした。これらの細胞を、初代ニューロスフィアへと発生させた。7〜10日後、ニューロスフィア数(この各々は、単一の幹細胞からクローン的に由来する)を計数した。
実施例1に記載された、妊娠中および/または産後期間におけるNSC数増加の二波パターンは、同じ期間におけるプロラクチンレベルのパターンと類似する。プロラクチン濃度は、妊娠の前半の間に高く、次いで、妊娠の終わりまで減少し、妊娠の終わりに、乳汁分泌および母性行動におけるその役割(Freemanら、2000に概説される)におそらく起因して、再度上昇する。プロラクチンは最初、生殖ホルモンとして同定されたが、次いで、プロラクチンの機能は、非常に多岐に渡ることが明らかとなった。中枢神経系(CNS)に対するプロラクチンの効果としては、母性行動、生殖行動、毛づくろい行動、給餌行動、睡眠−覚醒サイクル、視床下部ニューロンの刺激速度、ならびに神経伝達物質および神経ペプチドの代謝に対する作用が挙げられる。
SVZの神経幹細胞は、嗅球における持続的な神経発生の供給源であるので、本発明者らは、神経幹細胞に対する妊娠およびプロラクチンの効果がまた、嗅覚の神経発生に反映されるか否かを研究した。処女6〜8週齢CD1マウスまたは週齢の一致した妊娠6〜8週齢CD1マウスに、ブロモデオキシウリジン(BrdU)を注射して、妊娠7日目または分娩後7日目に、実施例1におけるように有糸分裂細胞を標識した。BrdU注射から4週間後、脳の種々の部分におけるBrdU標識化細胞の数を計数した。妊娠7日目に注射された妊娠マウスは、嗅球の顆粒細胞層およびドーパミン作用性の糸球体周囲細胞層の両方において、その処女対応動物よりも有意に多くのBrdU標識化細胞を有した。これらの結果は、妊娠が、嗅球へと移動する神経前駆細胞を形成することが知られている脳室下帯において神経幹細胞を増加させるという観察と一致する。
培養された神経幹細胞に対するプロラクチンの効果を決定するために、初代幹細胞培養物を、材料および方法に記載のようにして調製した。この細胞を、基本培地に加えて、EGF単独またはEGF+プロラクチンの存在下において、7日間インキュベートした。生じたニューロスフィア(初代ニューロスフィア)の数を計数し、そしてニューロスフィアを分離させて、第2代ニューロスフィアを形成させた。プロラクチン単独は、インビトロにおいてニューロスフィア数を有意に増加させることはなかったが(データは示さず)、この結果により、EGFがニューロスフィアを増加させる効果を、プロラクチンが増強し得ることが示される(図3)。さらに、初代ニューロスフィアが第2代ニューロスフィアを生成する能力もまた、プロラクチンの存在下において25%増加した(図3)。これにより初めて、プロラクチンが神経幹細胞に対して作用することが示される。
ニューロスフィアを、実施例4に記載のように、EGF単独またはEGF+30nMプロラクチンの存在下において培養した。7日後に、ニューロスフィアを基本培地のみ中で分化させ、ニューロン数を、チューブリンについて免疫染色することによって決定し、計数し、そして全細胞のパーセンテージとして表した。図4に示されるように、ニューロンのパーセンテージは、プロラクチンを含ませてニューロスフィアを増殖させた場合に、2倍高くなった。従って、プロラクチンは、神経幹細胞からのニューロン形成を増強し得る。
脳損傷に罹患した動物におけるプロラクチン投与の効果を決定するために、限局的虚血性損傷を、脳卒中のモデルとしてラットの脳に導入した。脳損傷の結果として、この動物は、運動皮質に病変を有し、そして前肢抑止試験(これは、前部新皮質領域の機能的統合性に関する高感度な測定である)において異常に行動した。次いで、この動物は、種々の試験因子を受け、そして前肢抑止試験に対するこれらの因子の効果および脳の解剖学的構造を評価した。コントロールとして、偽性コントロール群は、偽性の脳損傷を受け、そしていかなる試験因子も受けず、そしてビヒクルコントロール群は、脳損傷および人工脳脊髄液(CSF)の注入を受けた。各試験群が受けた処理を、以下にまとめる:
Claims (1)
- 神経幹細胞の数を増加させる条件下で、少なくとも1つの神経幹細胞に、有効量のプロラクチンを提供する工程を包含する、神経幹細胞の数を増加させるための医薬の製造におけるプロラクチンの使用。
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AU2002325711B2 (en) | 2007-08-23 |
WO2003024472A3 (en) | 2003-09-18 |
EP1430114A2 (en) | 2004-06-23 |
ES2383169T3 (es) | 2012-06-18 |
US7884072B2 (en) | 2011-02-08 |
AU2002325711C1 (en) | 2008-05-29 |
ATE541921T1 (de) | 2012-02-15 |
CA2460184A1 (en) | 2003-03-27 |
US7393830B2 (en) | 2008-07-01 |
JP2005501924A (ja) | 2005-01-20 |
US20080181873A1 (en) | 2008-07-31 |
US8222212B2 (en) | 2012-07-17 |
HK1067659A1 (en) | 2005-04-15 |
US20030054998A1 (en) | 2003-03-20 |
WO2003024472A2 (en) | 2003-03-27 |
AR036401A1 (es) | 2004-09-08 |
US20120329714A1 (en) | 2012-12-27 |
JP4906231B2 (ja) | 2012-03-28 |
US20110269681A1 (en) | 2011-11-03 |
EP1430114B1 (en) | 2012-01-18 |
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