JP6663509B2 - 神経幹細胞の分化促進用及び保護用の組成物、並びにそれを利用して神経再生を誘導する方法 - Google Patents
神経幹細胞の分化促進用及び保護用の組成物、並びにそれを利用して神経再生を誘導する方法 Download PDFInfo
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Description
2)前記神経細胞損傷誘発物質で処理された神経幹細胞に試験物質を投与する段階;及び
3)細胞形態(morphology)分析を介して、神経幹細胞の分化及び細胞死滅のいかんを確認する段階。
ベータアミロイドのうち42個のアミノ酸からなるAβ(1−42)が、Aβ(1−40)より凝集体を形成する傾向がさらに強く、特に、毒性が強いトリマーやテトラマーを形成する傾向が強く、アルツハイマー病の疾病状態と連関性がさらに高いと見られている。従って、Aβ(1−42)、特に、Aβ(1−42)のオリゴマー形態の存在下、神経幹細胞を保護しながら、神経幹細胞を分化させる組成物が望ましい。
特に、[化学式1]の化合物は、本発明において使用可能なMEK1/2抑制剤のうちでも、顕著に優秀な分化能、及びベータアミロイドからの保護効果を示した。例えば、[化学式1]の化合物は、AS703026に比べ、100倍以上さらに低濃度で顕著に優秀な分化能、及びベータアミロイドからの保護効果を示した。そのような本発明の[化学式1]の化合物の効果は、該化合物のMEK1/2抑制活性から予測されるところよりさらに顕著に優秀である。
2)前記神経細胞損傷誘発物質で処理された神経幹細胞に試験物質を投与する段階;及び
3)細胞形態(morphology)分析を介して、神経幹細胞の分化及び細胞死滅のいかんを確認する段階。
段階1:マウス胚芽神経幹細胞培養
段階1A:未分化状態でのマウス胚芽神経幹細胞培養
マウス胚芽14.5日の脳から神経幹細胞を分離し、N2培養培地に、10ng/ml塩基性線維芽細胞成長因子(bFGF:human basic fibroblast growth factor)(Peprotech,Princeton,NJ、cat#.100−18B)と20ng/mlヒト表皮成長因子(EGF:human epidermal growth factor)(Peprotech、cat#.AF−100−15)とを処理し、25cm2フラスコ(Nunc,Pittsburgh,PA)で、4日間、懸濁液状態で培養した。2日後から、ニューロスフェア形成を観察することができた。
Dulbecco’s Modified Eagle’s Medium(DMEM)/F12(1:1)(Gibco,cat#.11320033)、100μMプトレシン(Sigma,cat#.51799)、30nMセレナイト(Sigma,cat#.S5261)、20nMプロゲステロン(Sigma,cat#.P0130)、1.55mg/mlグルコース(d−(+)−glucose)(Sigma,cat#.G8270)、25μg/mlインシュリン(Gibco,cat#.12585014)、0.1mg/mlアポトランスフェリン(Sigma,cat#.T1147)、0.5mM Glutamax(Gibco,cat#.A1286001)、100IU/mlペニシリン(Gibco,cat#.15140122)、100μg/mlストレプトマイシン(Gibco,cat#.15140122)
単一細胞に分離して散布するとき、bFGFとEGFとを処理していないことを除いては、前記1Aと同一にマウス胚芽神経幹細胞を培養した。
段階1Aで培養されたマウス胚芽神経幹細胞に、多様な濃度の[化学式1]の化合物(以下、「トラメチニブ」ともいう)(Medchem express,Monmouth Junction,NJ、cat#.HY−10999A)及びAS703026(ピマセルチブ)(Selleckchem,Houston,TX、cat#.S1475)を毎日処理し、4日間培養した。
培養4日目、位相差顕微鏡で細胞形態を観察し、その結果を図1に示した。
段階1:マウス成体神経幹細胞の培養
段階1A:未分化状態でのマウス成体神経幹細胞の培養
8週齢マウス脳の脳室下帯部分から神経幹細胞を分離し、IPM培養培地に、20ng/mlヒト塩基性線維芽細胞成長因子(bFGF)と20ng/mlヒト表皮成長因子(EGF)とを処理し、24ウェルプレートで7日間懸濁液状態で培養した。4日後から、ニューロスフェア形成を観察することができた。
IPM培養培地:Neurobasal medium(Gibco,cat#.21103049)、B27 supplement(Gibco,cat#.A3582801)、Glutamax、100IU/mlペニシリン、100μg/mlストレプトマイシン
N2培養培地:Dulbecco’s Modified Eagle’s Medium(DMEM)/F12(1:1)、100μMプトレシン、30nMセレナイト、20nMプロゲステロン、1.55mg/mlグルコース(d−(+)―glucose)、25μg/mlインシュリン、0.1mg/mlアポトランスフェリン、0.5mM Glutamax、100IU/mlペニシリン、100μg/mlストレプトマイシン。
単一細胞に分離して散布するとき、bFGFとEGFとを処理していないことを除いては、前記1Aと同一にマウス成体神経幹細胞を培養した。
段階1で培養した神経幹細胞の培地を替え、各ウェルに、ベータアミロイド(Aβ)(Gibco,cat#.03112)10μMを処理した。比較群として使用するために、ベータアミロイドを処理していないウェルを残しておいた。
ベータアミロイド処理直後、トラメチニブは、10nM、100nMを添加し、メマンチン(Sigma,cat#.M9292)は、5μM、10μMを添加し、AS703026は、10μMをそれぞれ添加した。EGF、bFGF、ベータアミロイド及び試験物質を毎日処理しながら4日間培養した。
培養4日目、位相差顕微鏡で細胞形態を観察し、その結果を図2に示した。
段階1:マウス胚芽神経幹細胞培養
実験例1:段階1A及び1Bと同一方法で培養した。
実験例2:段階2と同一方法で、前述の段階1で培養されたマウス胚芽神経幹細胞に、ベータアミロイドを処理した。
ベータアミロイド処理直後、トラメチニブ100nM、メマンチン10μM、AS703026(ピマセルチブ)10μMを添加した。EGF、bFGF、ベータアミロイド及び試験物質を毎日処理しながら4日間培養した。
培養4日目、位相差顕微鏡で細胞形態を観察し、その結果を図3に示した。図3において上段は、マウス胚芽神経幹細胞にベータアミロイドを処理していない群であり、下段は、ベータアミロイドを10μM濃度で処理した群である。UD(undifferentiated)は、未分化胚芽神経幹細胞であり(試験物質未処理)、D(differentiated)は、分化された胚芽神経幹細胞である(試験物質未処理)。Aβ処理群において、試験物質処理いかんと関係なく、細胞がいずれも死滅し、試験物質の効果を確認することができなかった。
実験例1において、神経幹細胞が神経細胞に分化が誘導されたか否かということを確認するために、Tuj1及びDAPI(4’,6−diamidino−2−phenylindole)マーカーを利用した免疫細胞化学染色分析を行った。Tuj1(neuron−specific class III beta−tubulin)は、神経細胞特異的なマーカータンパク質であり、本実験において、ローダミン(rhodamine)を付着させ、赤色蛍光が示されるように標識し、DAPIは、細胞のDNAに結合し、核を青色蛍光に標識する染料である。
実験例4−1:マウス胚芽神経幹細胞における[化学式1]の化合物のTuj1及びTH発現分析
実験例1で分化誘導された細胞の種類を確認するために、quantitative RT−PCR(qRT−PCR)分析を介して、神経細胞特異的マーカーであるTuj1と、ドパーミン神経細胞マーカーであるTH(tyrosine hydroxylase)とのmRNA発現を確認した。
実験例1で形態分析を終えた後、各処理群の培地をいずれも除去し、TRIzol(R)(Invitrogen,Waltham,MA)をプレートに入れた後、5分間常温でインキュベーションし、細胞が良好に壊れるようにした。TRIzol(R)と共に細胞を集めてチューブで移し、クロロホルム(Sigma,cat#.366919)を入れた後、良好に混ぜて遠心分離し、上澄み液の澄んだ部分だけ新たなチューブに移した。イソプロパノール(Ducsan,GyunggiDo,Korea、cat#.67−63−0)を処理し、RNAが良好に分離されるように混ぜ、さらに遠心分離した後、上澄み液を除去し、ペレットだけ残した。75%エタノール(Ducsan、cat#、64−17−15)を処理し、さらに遠心分離し、上澄み液を除去した。三次滅菌水でペレットを良好に溶かし、mRNAを得て、55℃で10分間インキュベーションした後、−80℃でRNAを保管した。
RNAの濃度を測定し、実験各グループのRNAが2μgになるように計算し、Reverse transcription kit(Invitrogen,cat#.28025013)を利用して実験した。三次滅菌水、1pM oligo dT、1mM dNTPを入れ、65℃で5分間インキュベーションした後、5X first−strand buffer、10mM DTT、M−MLV逆転写酵素をさらに添加し、42℃で1時間、72℃で15分、4℃で30分インキュベーションした後、作られたcDNAを−20℃で保管した。
前述の段階で作られたcDNA 1μl、プライマー1pM、三次蒸溜水、Rotor−Gene SYBR(R)Green(Qiagen,Venlo,Netherlands、cat#.204074)を入れて良好に混ぜた後、Rotor−Gene Q(Qiagen)機械を利用してPCRを行った。使用されたプライマー(Bioneer,Daejeon,Korea)は、下記表2の通りである。
[化学式1]化合物が、ドパーミン神経細胞以外に、他種の神経細胞でも分化を誘導する否かということを確認するために、qRT−PCR分析を介して、コリン性神経細胞マーカーであるChAT(choline acetyltransferase)、運動神経細胞マーカーであるIsl1(Islet1)、GABA性神経細胞マーカーであるGad1(glutamate decarboxylase 1)のmRNA発現を確認した。
実験例5−1:マウス胚芽神経幹細胞におけるMEK1,MEK2発現抑制
MEK1、MEK2の発現程度による神経幹細胞の神経細胞への分化能を確認した。このとき、MEK1、MEK2の発現が調節された細胞は、下記のように製造したものを利用した。
MEK1、MEK2の活性化による神経幹細胞の神経細胞への分化能を確認するために、MEK1とMEK2とが常時活性化されるように突然変異を有するconstitutively active MEK1(CAMEK1),constitutively active MEK2(CAMEK2)プラスミドを利用して実験した。具体的には、実験例1、段階1Aでのように培養されたマウス胚芽神経幹細胞をプレートに良好に散布(seeding)し、24時間培養後、前記細胞に、1μg/mlのCAMEK1,CAMEK2を、Lipofectamineを使用してトレンスフェクションし、CAMEK1とCAMEK2とのうちいずれか一つ、またはCAMEK1とCAMEK2とのいずれも発現された神経幹細胞を製造した。そのように作られた神経幹細胞を、4時間後、さらにEGFとbFGFとが含まれていないN2培養培地に培地を替え、4日間さらに培養した後、RNA及びタンパク質を抽出し、quantitative RT−PCR(qRT−PCR)及びウェスタン・ブロッティングを行い、MEK1、MEK2の活性化が、神経幹細胞から神経細胞への分化能に及ぼす影響を確認し、図8Cに示した。
成体幹細胞においても、MEK1とMEK2との抑制が、神経幹細胞の分化を誘導するか否かということ、ベータアミロイドがある状況においても、同一効果があるか否かということを確認するために、次のように実験を進めた。
トラメチニブ以外の他のMEK1/2抑制剤も、神経幹細胞の分化誘導効果及び保護効果があるか否かということを認するために、マウス胚芽神経幹細胞に各化合物を処理した。具体的には、実験例1の段階1Aでのように培養されたマウス胚芽神経幹細胞に、MEK1/2抑制剤として知られたAZD8330(Selleckchem,cat#.S2134)、PD184352(Selleckchem,cat#.S1020)、レファメチニブ(Sellechchem,cat#.S1089)、PD318088(Selleckchem,cat#.S1568)、Binimetinib(Selleckchem,cat#.S7007)及びAS703026を、0.1μM、1.0μM、10μMでそれぞれ処理して培養した。比較のために、トラメチニブも、同濃度で処理した。培養2日目、位相差顕微鏡で細胞形態を観察し、その結果を図10Aに示した。図10Bは、各グループの細胞に対して、Tuj1 mRNA発現を分析した結果である。
実験例2、段階1Aでのように培養した成体神経幹細胞に、実験例2の段階2でのように、ベータアミロイド10μMを処理して細胞毒性環境を誘発し、MEK1/2抑制剤であるAS703026(10μM)、AZD8330(1μM)、PD318088(1μM)、ビニメチニブ(10μM)、レファメチニブ(1μM)、PD0325901(10μM)、RO5126766(10μM)を、それぞれ実験例6で最も分化を良好に誘導した濃度で処理して培養した。比較のために、トラメチニブ0.1μM処理群と、MEK2に比べ、MEK1に対して選択的な阻害剤として知られたコビメチニブ10μM処理群と、を追加し、ベータアミロイド処理を行わず、各化合物を培養した群も、追加した。培養2日目、位相差顕微鏡で細胞形態を観察し、その結果を図11に示した。
前述の実験結果を介して、MEK1、MEK2を同時に抑制する物質のうち特定物質が神経幹細胞から神経細胞への分化を誘導し、ベータアミロイドから神経幹細胞を保護する効果があり、特に、トラメチニブが顕著に優秀な効果を示すということを確認した。そのような効果を、神経退行性疾患モデルマウスでも確認するために、神経退行性疾患のうち最も一般的な疾患であるアルツハイマー病の症状、特に、体性感覚皮質のlayer 5及び海馬移行部(subiculum)での神経細胞の退行及び死滅を示す動物モデル(Oakley et al., (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation, J Neurosci. 26 (40): 10129-10140)である5XFADマウスを利用し、トラメチニブの神経再生効能及び治療効能を確認した。
実験例8において、トラメチニブを投与した5XFADマウスの大脳皮質及び海馬移行部での神経細胞数の増加が、トラメチニブによる神経細胞新生誘導効果を介して示されたものであるか否かということを確認するために、神経幹細胞から神経細胞に分化する過程中に示される多様な細胞のマーカーを利用し、免疫組織化学染色方法で確認した。
実験例8の5XFADマウスの脳組織スライドに、Tuj1抗体を4℃で1日インキュベーションさせ、翌日、FITC(fluorescein isothiocyanate)−二次抗体(Invitrogen,cat#.a21121)を常温で1時間インキュベーションさせ、蛍光染色法で染色した。大脳皮質のうち体性感覚皮質部分の蛍光顕微鏡写真結果を図15に示した。図15において、矢印(→)で表示した部分は、Tuj1が染色された細胞を示し、矢印の頭(▼)で表示したものは、ベータアミロイド凝集によるプラークを示す。ビークル処理群とトラメチニブ処理群とのいずれにおいても、ベータアミロイドプラークが存在していたが、特に、トラメチニブ0.1mg/kgを投与した群において、ビークルグループと対比し、類似程度のベータアミロイドプラークの存在にもかかわらず、Tuj1が染色された細胞数が顕著に増加しているということを確認した。
マウス歯状回(dentate gyrus)の顆粒細胞下帯(SGZ)において、神経細胞新生過程が活性化されれば、神経幹細胞が非対称分裂が起こり、その結果として、Type 2形態の細胞が最も初期に生成される。Type 2形態の細胞は、小さい細胞体(soma)と非定型の細胞核とを有しており、短く水平方向に細胞が位置しており、ネスチンやDcxを発現している。Type 3形態の細胞は、Type 2形態の細胞がさらに分化した形態の細胞をいうが、神経母細胞(neuroblast)ともいう。Type 3細胞は、神経阿膠細胞系譜(glial cell lineage)ではなく、神経細胞系譜(neuronal cell lineage)に分化される分化初期の細胞である。Type 3細胞は、マウス歯状回の顆粒細胞下帯において、果粒層側に若干移動した位置に存在し、細胞形態は、Type 2細胞と異なり、水平方向から垂直方向の形態に変わっている形態である。マウス歯状回の顆粒細胞下帯に、Type 2細胞とType 3細胞とが存在することは、神経細胞新生がなされていることを意味する。
神経細胞の新生が起こるためには、神経幹細胞の非対称分裂(asymmetric division)がまず起こらなければならないが、それを確認するために、次のように実験を行った。
5XFADマウスの大脳皮質及び海馬移行部において、トラメチニブが神経細胞の保護効果を有するか否かということを確認するために、細胞死滅(apoptosis)を確認することができる免疫組織化学染色方法であるTUNEL(terminal deoxynucleotidyl transferase dUTP nick end labeling)assayを行った。TUNEL assayは、細胞死滅が起こるとき、壊れているDNAの3’−ヒドロキシ末端を染色する染色法であり、組織内で死滅している細胞を目で確認することができる。
実験例8の5XFADマウスの脳組織スライドに、Tuj1抗体及びカルビンジン抗体(Cell signaling,cat#.13176)を、4℃で1日インキュベーションさせ、翌日FITC(fluorescein isothiocyanate)−二次抗体またはローダミン−二次抗体を、常温で1時間インキュベーションさせて蛍光染色法で染色した。小脳プルキンエ細胞層(Purkinje cell layer)部分を蛍光顕微鏡で観察した結果の写真を図18に示した。各処理群別において、2個(Tuj1染色)または3個(カルビンジン染色)のスライドに係わる写真を添付した。
神経退行性疾患治療用薬物は、中枢神経系に作用する薬物であるので、血液脳障壁(blood brain barrier)を通過し、脳で作用することができる否かということが問題になる。MEK1/2抑制剤のうち、AS703026のような物質は、マウスのBBBを効果的に通過し、マウス脳においてMEKを抑制する結果、phosphorylated ERK(pERK:ERKの活性化された形態)の発現を低減させると知られている(Shaw et al., (2012) Evaluation of brain pharmacokinetics as a potential differentiation factor for the MEK inhibitors, MSC2015103 and pimasertib, Abstract LB-456, American Association for Cancer Research Annual Meeting, Chicago, IL)。本実験例においては、MEK1/2抑制剤であるトラメチニブが、5XFADマウスに経口投与されたとき、脳に伝達され、前述の実験例のような効果を示したか否かということを確認するために、脳組織でのpERK発現レベルを測定した。
アルツハイマー病気の最大病理学的特徴は、ベータアミロイドの蓄積であるので、トラメチニブが、ベータアミロイド蓄積を減少させる効果があるか否かということを確認した。実験例12から得られた5XFADマウス脳の半球(hemisphere)の良好にすりつぶされア粉末を利用し、Aβ(1−40)とAβ(1−42)との量を、ELISA(enzyme-linked immunosorbent assay)方法で確認した。次のように、ELISA kit(Invitrogen,MA、cat#.KHB3442)を利用して実験を行った。まず、5M guanidine−HCl溶液を入れ、ピペットでマウス脳の粉末を良好に懸濁し、16,000xg、4℃で遠心分離し、上澄み液を集めた。タンパク質の濃度を測定した後、30〜50μgのタンパク質が100μlになるように、dilution バッファを入れて準備した。Aβ(1−40)抗体あるいはAβ(1−42)抗体を96ウェルプレートにそれぞれ100μlずつ入れ、常温で2時間インキュベーションした後、溶液を除去し、4回洗浄用バッファで洗浄した。HRPが付いた二次抗体をそれぞれ100μlずつ入れ、常温で30分間インキュベーションした。また、溶液を除去し、洗浄用バッファで4回洗浄した。その後、準備しておいたタンパク質を、100μlずつ各ウェルに入れ、暗いところで30分間インキュベーションした後、stop溶液を100μlさらに添加して反応を止めた。その後、感光機械を利用し、450nmで感光反応を測定した。吸光度数値を、基準濃度対比で換算し、測定された各タンパク質の濃度を計算した。タンパク質総量(30〜50μg)対比で、Aβ(1−40)、Aβ(1−42)の量を計算し、またAβ(1−40)対比で、Aβ(1−42)の量を計算した。グループ当たり3匹での数値の平均値を求め、図20に示した。図20から分かるように、トラメチニブを処理したグループにおいて、ビークル処理グループより、Aβ(1−42)/Aβ(1−40)の量が小さくなるということを確認した。
Claims (11)
- トラメチニブを有効成分として含む、神経細胞の損失または損傷によって生じる神経退行性疾患の治療用薬学組成物であって、
前記神経退行性疾患が、痴呆、アルツハイマー病、血管性痴呆、前頭側頭葉痴呆、レビー小体痴呆、ハンチントン病、筋萎縮性側索硬化症(ルーゲーリック病、ALS)、原発性側索硬化症、進行性延髄麻痺(PBP)、進行性筋萎縮症(PMA)、仮性延髄麻痺、遺伝性強直性下半身麻痺(HSP)、及び小脳性運動失調症からなる群から選択されることを特徴とする、薬学組成物。 - 神経退行性疾患の治療が、
神経幹細胞を神経細胞に分化させることにより神経再生を誘導してなされる、
請求項1に記載の薬学組成物。 - 神経退行性疾患の治療が、
さらに、ベータアミロイドによる細胞毒性から神経幹細胞及び神経細胞を保護することによりなされる、
請求項2に記載の薬学組成物。 - 神経幹細胞から分化される神経細胞が、
ドーパミン神経細胞、GABA性神経細胞、コリン性神経細胞、及び運動神経細胞からなる群から選択される1以上であることを特徴とする請求項2に記載の薬学組成物。 - 神経退行性疾患がアルツハイマー病であることを特徴とする請求項1に記載の薬学組成物。
- 神経退行性疾患が血管性痴呆であることを特徴とする請求項1に記載の薬学組成物。
- 神経退行性疾患が筋萎縮性側索硬化症(ルーゲーリック病、ALS)であることを特徴とする請求項1に記載の薬学組成物。
- 神経退行性疾患がハンチントン病であることを特徴とする請求項1に記載の薬学組成物。
- トラメチニブが、1日0.1mgないし2mgの用量で投与されることを特徴とする請求項1〜8のいずれか1項に記載の薬学組成物。
- トラメチニブが、1日0.1ないし1mgの用量で投与されることを特徴とする請求項9に記載の薬学組成物。
- トラメチニブが、1日0.1ないし0.5mgの用量で投与されることを特徴とする請求項10に記載の薬学組成物。
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