Elucidation of the role of CGRP in migraine pathophysiology and application of oligonucleotide therapeutics to migraine treatment

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07849
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Keio University
• Principal Investigator: Shibata Mamoru 慶應義塾大学, 医学部(信濃町), 客員教授 (60286466)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 片頭痛 / カルシトニン遺伝子関連ペプチド / 三叉神経節ニューロン / 感作 / 身体活動性低下 / 光過敏 / 後発症状 / ノイロトロピン

Outline of Final Research Achievements

We have shown that cortical spreading depression (CSD) causes trigeminal sensitization, photophobia, and hypomotility in mice. The calcitonin gene-related peptide (CGRP) receptor blocker, olcegepant, and sumatriptan suppressed these abnormalities. The CSD-induced hypomotility outlasted trigeminal sensitization, reminiscent of migraine postdrome. This protracted hypomotility proved to be ameliorated by CGRP receptor blockade and Neurotropin. CSD did not significantly change the density of CGRP mRNA-synthesizing neurons in the ipsilateral trigeminal ganglion (TG). However, the cell sizes of CGRP mRNA-synthesizing TG neurons were significantly larger at 48 h and 72 h post-CSD. We deduce that the CSD-induced upward cell size shift of CGRP mRNA-synthesizing TG neurons might be causative of greater disease activity and/or less responsiveness to CGRP-based therapy. Our research has opened up the possibilities of nucleic acids therapeutics-based approach to migraine.

Free Research Field

頭痛医学

Academic Significance and Societal Importance of the Research Achievements

CGRPに対する核酸医薬の効果を検討するための片頭痛モデルを作成した。片頭痛の後発症状のモデル動物を作成し、後発症状の身体活動性の低下にノイロトロピンとCGRP受容体拮抗薬olcegepant抑制が有効である可能性を示した。CSDを用いた片頭痛モデルで、三叉神経節ニューロンでのCGRP mRNA産生状態に変化が認められたことはCGRPに対する核酸医薬が片頭痛に対する有効な治療戦略である可能性を示唆していると考えられる。また、CGRP mRNA産生を行う細胞が遅発性に変化したことは、片頭痛再発予防治療を考える上で重要な所見と考えられる。