JP4993900B2 - 記憶障害抑制剤 - Google Patents
記憶障害抑制剤 Download PDFInfo
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- JP4993900B2 JP4993900B2 JP2005342946A JP2005342946A JP4993900B2 JP 4993900 B2 JP4993900 B2 JP 4993900B2 JP 2005342946 A JP2005342946 A JP 2005342946A JP 2005342946 A JP2005342946 A JP 2005342946A JP 4993900 B2 JP4993900 B2 JP 4993900B2
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- memory
- melatonin
- memory impairment
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Description
(1)メラトニン若しくはその誘導体、その薬学的に許容可能な塩、又はこれらの溶媒和物を含む、記憶障害抑制剤。メラトニン又はその誘導体は、
次式I:
(I)
(式中、Xはハロゲン原子又は水素原子を表し;R1は水素原子、置換又は非置換のC1−6−アルキル基、置換又は非置換のC2−6−アルケニル基、置換又は非置換のC2−6−アルキニル基、置換又は非置換の芳香族基、置換又は非置換のアラルキル基、置換又は非置換のアシル基、置換又は非置換のアリールスルホニル基、置換又は非置換のC1−6−アルキルスルホニル基、置換又は非置換のC2−7−アルコキシカルボニル基、又は水酸基を表し;R2は置換又は非置換のC1−21−アルキル基を表し;R3、R5及びR6は、同一又は異なり、水素原子又はハロゲン原子を表し;R4は水素原子、又は置換又は非置換のC1−6−アルキル基を表す。)で示される化合物又はその塩で示されるものでもよい。さらに、上記記憶障害抑制剤は、加齢による記憶障害を抑制するためのものがあげられる。
(1)記憶障害のメカニズム
記憶は、記銘、保持、追想(再認)という一連の精神的作用によって維持されており、この過程のどこかに異常が起これば記憶は障害される。さらに記憶はそこに関わる遺伝子の違いと遺伝子変異体の示す記憶保持の特性から、短期記憶(short-term memory)(STM)、中期記憶(middle-term memory)(MTM)、麻酔耐性記憶(longer-lasting anesthesia-resistant memory)(ARM)、長期記憶などの記憶成分に分類されている(図1b)。記憶障害には、老人性痴呆症として知られている加齢に伴う学習・記憶能力の低下、すなわち、加齢性記憶障害が知られている。加齢性記憶障害(age-related memory impairment)(AMI)は、多くの動物種において観察されている。AMIは、神経ペプチドをコードするamn遺伝子が関与する疾患であり、中期記憶の特異的な低下が原因であると考えられる。
本発明の抑制剤は、このような記憶障害のいずれにも適用が可能であり、加齢性記憶障害に対して好ましく適用することができる。
記憶障害が抑制されたか否か、すなわち記憶障害が改善又は予防されたか否かを調べるための試験には、様々な動物モデルを用いることができるが、以下の点でショウジョウバエが好ましい。まず、ショウジョウバエと哺乳類は学習記憶過程に多くの共通した分子メカニズムを有しており、ショウジョウバエでもヒト同様に記憶障害が見られる。さらに、ショウジョウバエは寿命が約1ヶ月と短く、寿命が年単位の哺乳類モデルより適している。特に、加齢性の記憶障害等の解析には、寿命が短いショウジョウバエをモデルとして用いるのが好ましい。
記憶障害の抑制効果の有無は、学習記憶行動を解析することにより検討することができる。学習記憶行動を解析するには、例えば行動遺伝学的解析を行うこともできる。具体的には、匂い条件付けパラダイム(a single olfactory conditioning paradigm)の手法を採用することができるが本手法に限定されない。匂い条件付けパラダイムは、例えば、3-オクタノールと4-メチルサイクロヘキサノールという二種類物質のうち、いずれか1つの物質の匂いを、電気ショック(60V)を与えながら1分間嗅がせた後、他方の物質の匂いを今度は電気ショックなしで1分間嗅がせて、どちらの物質による匂いが危険であるかを弁別学習させることによる。この弁別学習後任意の時間に記憶テストを行う。記憶テストは、2種類の匂いを左右それぞれから流し、いずれか一方の匂いを選択させて(図1a)、2種類の匂いを電気ショックの有無で交互に組み合わせて1回の実験とする。多くの場合、ショウジョウバエは電気ショックを与えられながら嗅がせられた匂いを避け、もう一方の匂いを選択するが、学習してからの時間、遺伝子の変異などの様々な要因で選択を間違える場合がある。そのため、電気ショックと匂いの組み合わせを正しく覚えたショウジョウバエと、間違ったショウジョウバエの数を数え、記憶係数を算出し、記憶係数が高ければ高いほど記憶が良好であると判断できる。
メラトニンの誘導体は次式I:
(I)
(式中、Xはハロゲン原子又は水素原子を表し;R1は水素原子、置換又は非置換のC1−6−アルキル基、置換又は非置換のC2−6−アルケニル基、置換又は非置換のC2−6−アルキニル基、置換又は非置換の芳香族基、置換又は非置換のアラルキル基、置換又は非置換のアシル基、置換又は非置換のアリールスルホニル基、置換又は非置換のC1−6−アルキルスルホニル基、置換又は非置換のC2−7−アルコキシカルボニル基、又は水酸基を表し;R2は置換又は非置換のC1−21−アルキル基を表し;R3、R5及びR6は、同一又は異なり、水素原子又はハロゲン原子を表し;R4は水素原子、又は置換又は非置換のC1−6−アルキル基を表す。)で示される化合物又はその塩をいう。
式Iで表される化合物は、公知の化学合成により、あるいは市販品(Sigma社)としても得ることができる。
式Iで表される化合物、その薬学的に許容可能な塩又はこれらの溶媒和物(例えばメラトニン)を含む餌で飼育・加齢させた加齢体群(メラトニン摂取群とする)の記憶スコアは、対照となる通常の餌で飼育した加齢体群より顕著に高い(図3)。これは、例えば、以下のようなショウジョウバエを用いた実験手法により確認することができる。
本発明の記憶障害抑制剤は、メラトニン若しくはその誘導体、その薬学的に許容可能な塩、又はこれらの溶媒和物を有効成分として含む。
メラトニンは適当量のエタノールに溶解した後100μg/mlとなるよう餌に混入し、野生型ショウジョウバエに羽化後から摂取させた(メラトニン摂取群)。対照群ではメラトニンを含まない溶媒(エタノール)のみを同量餌に混入し摂取させた(対照群)。メラトニン摂取群、対照群は3〜4日ごとに新しいエサに変えながら20日間飼育した。記憶障害の抑制効果の有無は、学習記憶行動を解析することにより検討した。3-オクタノールと4-メチルサイクロヘキサノールという二種類物質のうち、いずれか1つの物質の匂いを、電気ショック(60V)を与えながら1分間嗅がせた後、他方の物質の匂いを今度は電気ショックなしで1分間嗅がせて、どちらの物質による匂いが危険であるかを弁別学習させる。学習後1時間で記憶テストを行い、いずれか一方の匂いを選択させた。
羽化直後から加齢性記憶障害が顕著となる20日齢まで、任意の日齢からメラトニンメラトニン摂取を開始し、いつから摂取を始めれば加齢性記憶障害の改善効果が得られるか、メラトニン摂取群、対照群の20日齢で1時間記憶を比較した。
Claims (1)
- メラトニン、その薬学的に許容可能な塩、又はこれらの溶媒和物を含む、加齢による記憶障害の抑制剤。
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