Effect of neonatal exposure of methotrexate on cerebellum development in rats

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K12187
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 63030:Chemical substance influence on environment-related
• Research Institution: Okayama University of Science
• Principal Investigator: Akihiko Sugiyama 岡山理科大学, 獣医学部, 教授 (00432609)
• Co-Investigator(Kenkyū-buntansha): 野原 正勝 岡山理科大学, 獣医学部, 助教 (70649996)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: メトトレキサート / ラット新生児 / 小脳外顆粒細胞 / アポトーシス / 細胞増殖抑制 / 細胞周期停止 / プルキンエ細胞樹状突起 / 葉酸製剤

Outline of Final Research Achievements

Apoptosis of external granular cells induced by methotrexate (MTX) administration in infant rats was associated with mitochondrial pathway and Fas - Fas ligand pathway, and cell proliferation inhibition of them was associated with cell cycle arrest. Expression of Genes related to external granular cells migration, development of Purkinje cell dendrites and synaptogenesis, were regressed in the cerebellum of MTX-exposed infant rats. MTX exposure in six-day-old rats induced cerebellar hypoplasia and incomplete development of Purkinje cell dendrites in 21-day-old rats, and these histopathological changes were also observed in 70-day-old rats. This result suggests that the effects on cerebellum of MTX exposure in the infant period may continue until the maturation period.

Free Research Field

獣医病理学

Academic Significance and Societal Importance of the Research Achievements

葉酸代謝拮抗剤メトトレキサート (MTX)による治療を受けたヒト小児急性白血病患者に小脳低形成の発症が認められているにも関わらず、MTXが小脳の発達に及ぼす詳細な有害作用機序は未解明であった。本研究成果はMTXのラット新生児期曝露による小脳傷害の発症機構のみならず、その後の小脳の発達への影響の全貌解明に迫る有意義なものである。また、MTXは生体内における葉酸代謝を拮抗する作用を有することから、本研究成果は一薬剤の小脳の発達へ及ぼす有害作用機構の解明にとどまらず、葉酸代謝異常という病態が小脳の発達に及ぼす影響の解明にも大きく貢献しているといえる。