2023 Fiscal Year Final Research Report

Molecular mechanism of pH-related ion channels in cerebral infarction using pH image

Research Project

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Project/Area Number	21K09189
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 56010:Neurosurgery-related
Research Institution	Nihon University
Principal Investigator	IGARASHI Takahiro 日本大学, 医学部, 医師職等特別職 (20468747)
Co-Investigator(Kenkyū-buntansha)	大島秀規日本大学, 医学部, 准教授 (20328735) 須磨健日本大学, 医学部, 准教授 (20526115) 大谷直樹日本大学, 医学部, 准教授 (20573637) 梶本隆太日本大学, 医学部, 助教 (90883041)
Project Period (FY)	2021-04-01 – 2024-03-31
Keywords	脳血管障害 / pH / 酸感受性イオンチャネル / Epac
Outline of Final Research Achievements	In stroke, it goes without saying that "time" since onset is crucial, but the "gravity" of ischemic damage is also an important factor. pH change is an important factor in evaluating the "gravity" of ischemia. Chemical Exchange Saturation Transfer technology holds promise for tissue pH based on proton exchange rate changes. In the conventional penumbra, distinct sites with significant pH changes (metabolic penumbra: MP) and sites with minimal pH changes (benign oligemia: BO) were identified. Histological evaluation using ssDNA staining revealed differences in the "gravity" of injury between the MP and BO regions after reperfusion. Furthermore, observing subsequent changes following early ischemic metabolic penumbra pH changes, we noted a correlation between pH changes, hemorrhagic transformation, and exchange proteins activated by cyclic AMP (Epac) activity. Additionally, behavioral observations in rats post-stroke revealed that pH changes post-ischemia influence subsequent seizure.
Free Research Field	脳血管障害
Academic Significance and Societal Importance of the Research Achievements	虚血早期の画像上のpH変化と組織傷害に明確な関連性を見出すことができた。組織pH変化は痛みや味覚の伝達に関与しており，脳内では海馬の神経新生に重要な役割を果たすことが解明されている。また，Epacは神経伝達物質によって引き起こされるシグナル伝達や神経可塑性などの神経機能に積極的に関与することが知られている。本研究の成果より，虚血によるpH変化とEpac2の発現に関連性を認めた。これは，虚血に伴うpH変化でEpac2が過剰に活性化され，機能的（異常）シナプス形成に関与していると考える。pH制御は，脳卒中急性期の生命・機能予後の改善だけでなく，慢性期のてんかん発症や重症化の抑制に寄与すると考える。