2023 Fiscal Year Final Research Report
Development of Adverse Events-free Local Anesthetics in Cryo-EM Structural Determination of Sodium Channels
| Project/Area Number |
21K19517
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
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| Research Institution | Tohoku University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
杉野 繁一 東北大学, 大学病院, 准教授 (00423765)
渡部 聡 東北大学, 多元物質科学研究所, 助教 (50432357)
木下 賢吾 東北大学, 東北メディカル・メガバンク機構, 教授 (60332293)
鈴木 隆史 東北大学, 医学系研究科, 准教授 (70508308)
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| Project Period (FY) |
2021-07-09 – 2024-03-31
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| Keywords | 局所麻酔薬 / ナトリウムチャネル / 構造生物学 |
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| Outline of Final Research Achievements |
Local anesthetic systemic toxicity characterized by convulsions and circulatory collapse is a serious complication of local anesthetics. Local anesthetics currently used in clinical practice indiscriminately block all Na channels, producing adverse effects in the central nervous system and heart.The previous basic studies have revealed that there are nine isoforms of voltage-gated Na channels (Nav channels), and three of them, Nav1.7, Nav1.8, and Nav1.9, are localized in peripheral nerves and involved in pain transmission. The purpose of this study was to obtain structural information using cryo-EM, and to search for molecules that selectively bind to only three channels, Nav1.7, Nav1.8, and Nav1.9, leading to the discovery of new local anesthetic drugs. We focused on the Nav1.8 channel based on exsome analysis of patients with congenital indifference to pain. However, our research did not progress as expected, and we had to abandon our initial goal.
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| Free Research Field |
麻酔科学・疼痛医学
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| Academic Significance and Societal Importance of the Research Achievements |
良質の局所浸潤麻酔や神経ブロックは患者だけではなく，外科医療からの早期回復に必須である．近年は超音波ガイドによる神経ブロックの技術向上とPatient Controlled Analgesiaなどによる局所麻酔薬の投与方法の工夫で，区域麻酔は確実性と安全性は飛躍的に向上した．しかし，局所麻酔薬は痺れ，感覚低下，さらに運動麻痺を伴うため，リハビリテーションの妨げや患者の医療に対する満足度を下げてしまう．さらにけいれんや循環虚脱を特徴とする局所麻酔薬中毒は重篤な合併症である．本研究ではこのような合併症とは無縁な局所麻酔薬分子を探索・創薬する予定であったが，期待した結果は得られなかった．
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