Highly efficient neuronal regeneration through regulation of protease activity for the treatment of ischemic brain injury

2023 Fiscal Year Final Research Report

• Project/Area Number: 20KK0381
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: Kawashita Eri 京都薬科大学, 薬学部, 助教 (80509266)
• Project Period (FY): 2021 – 2023
• Keywords: 脳梗塞 / 新生児低酸素性虚血性脳症 / 線溶 / ニューロセルピン / α2-アンチプラスミン / セルピン

Outline of Final Research Achievements

α2-Antiplasmin (α2AP) and neuroserpin (NSP), members of the serine protease inhibitor (serpin) family, are known as principal physiological inhibitors of plasmin and tissue plasminogen activator (tPA), respectively. In this international joint research study, we demonstrated a protective effect of NSP against brain damage in adult stroke and mild neonatal hypoxic-ischaemic encephalopathy (HIE) mouse models by suppressing ER stress and/or oxidative stress. In addition, we found that α2AP deficiency promotes endogenous neurogenesis in the subventricular zone in a stroke mouse model. These findings suggest that combination of exogeneous neuroserpin and α2AP inhibition could be a candidate pharmacotherapy of stroke and neonatal HIE.

Free Research Field

薬学

Academic Significance and Societal Importance of the Research Achievements

脳梗塞や新生児HIEなどの虚血性脳疾患に対する治療において、発症後に失われた神経機能を再生・回復させる薬物治療は存在しない。脳虚血による神経機能障害は高確率で発生し、患者やその家族に対して大きな精神的・経済的苦痛をもたらすことから、虚血性脳疾患に対するneural replacement療法の開発は重要課題の一つである。本研究により、脳梗塞や新生児HIEにおいて、NSP投与による神経保護効果およびα2AP欠損による神経新生促進効果が明確になった。この成果は、脳梗塞および新生児HIEを含む虚血性疾患におけるneural replacementの高効率化を目指した薬物療法の実現化に繋がる。