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T型カルシウムチャネル活性化薬SAK3の神経保護作用と神経新生促進作用に関する研究

許 晶 東北大学

2021.03.25

概要

【背景・目的】アルツハイマー型認知症 (AD) は認知症において最も多い疾患であり、根本的な治療薬はない。当研究室では、AD の認知障害を改善する薬として T 型電位依存性カルシウムチャネル (T-VGCC) の活性化薬である SAK3 (ethyl-8′-methyl-2′,4-dioxo-2-(piperidin-1-yl)-2′H-spiro[cyclopentane-1,3′-imidazo[1,2-a]pyridin]-2-ene-3-carboxylate) を創製した。T-VGCC は、てんかん、神経疼痛、睡眠などの病態生理に関与する。しかし、神経細胞の生存と新生における T- VGCC の役割は不明である。本研究では、T-VGCC 活性化薬 SAK3 の両側総頚動脈閉塞 (BCCAO) マウスに対する神経保護作用と嗅球摘出 (OBX) マウスに対する抗うつ作用を検討し、神経細胞の生存と新生における T-VGCC の役割を解明することを目的とする。

【方法】BCCAO マウスでは虚血後 2 週間で海馬 CA1 領域の神経細胞が特異的に変性脱落する。虚血後、24 時間後から 10 日間 SAK3 (0.1〜1.0mg/kg) を経口投与して、海馬 CA1 領域の神経細胞死の解析、行動薬理試験を行った。嗅球摘出マウスは術後 2 週間目からうつ症状を呈する。うつ症状を確認後に 14 日間 SAK3 (0.1〜1.0mg/kg) を経口投与して、うつ症状および海馬における神経新生を解析した。

【結果】BCCAO マウスでは SAK3 の慢性投与によって海馬 CA1 領域の神経細胞死は用量依存性に抑制され、約 8 割の神経が生存した。同時に、虚血に伴う記憶学習障害も改善した。BCCAO 処置、24 時間後の海馬では神経細胞生存に重要なプロテインキナーゼであるプロテインキナーゼ B (Akt) リン酸化反応が有意に低下したが、SAK3 急性投与により改善した。これら作用はムスカリン性アセチルコリン受容体阻害薬ではなく、ニコチン性アセチルコリン受容体(nAChR) 選択的阻害薬の前投与により消失した。

次に、うつ様行動、海馬神経新生に対する SAK3 の効果を OBX マウスで検討した。SAK3 慢性投与は、OBX マウス認知機能障害とうつ病様行動を改善した。また、OBX マウスでは術後 4 週間後の海馬歯状回 (DG) における神経新生が有意に抑制された。神経新生抑制は SAK3 慢性投与によって有意に回復した。ヒトにおいてはうつ病の発症に神経栄養因子 (BDNF) の機能低下が観察されている。OBX マウスの海馬領域においてもBDNF の発現低下が認められた。 BDNF 発現低下は、SAK3 慢性投与によって有意に回復した。BDNF 発現の亢進作用には、カルシウム/カルモデュリン依存性プロテインキナーゼである CaMKIIおよびCaMKIV の活性化とcAMP 応答配列結合タンパク質 (CREB) のリン酸化上昇が相関していた。SAK3 のこれらの効果は、T-VGCC 選択的な阻害剤である NNC55-0396 の前投与によって完全に抑制された。さらに、SAK3 は神経細胞の増殖と分化の両方を刺激することを in vivo で確認した。

【結論】認知障害を改善する薬として開発中である SAK3 には強力な神経保護作用と神経新生促進作用があることが分かった。SAK3 は脳内で ACh の遊離を促進すること、nAChR を介する Akt 活性化反応は神経生存シグナルに関与することが知られている。SAK3 の神経保護効果にも nAChR 活性化反応が関与すると考えられる。次に OBX マウスに対する SAK3 の抗うつ作用が見出された。抗うつ作用には CaMKII/CaMKIV/CREB/BDNF シグナルが関与すると考えられる。さらに、BDNF の下流シグナルである Akt も神経幹細胞の生存と分化に関与すると考えられる。これらの神経生存シグナル、神経新生シグナルの亢進作用もSAK3 の認知機能改善作用に寄与することから、アルツハイマー病治療薬候補として有益な薬理作用であることが示された。

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参考文献

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