Search for the TLR4 inhibitor as a novel treatment strategy for preterm birth

• Project/Area Number: 17K16847
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: Kyoto University
• Principal Investigator: Chigusa Yoshitsugu 京都大学, 医学研究科, 助教 (80779158)
• Research Collaborator: Word Ruth Ann University of Texas, Southwestern Medical Center
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 早産 / 羊膜 / TLR4

Outline of Final Research Achievements

The IC50 of 6 compound was assessed, and compound C (econazole nitrate), and compound D (parthenolide) had the lowest IC50, suggesting they are potent TLR4 inhibitors. Both econazole nitrate and parthenolide significantly inhibited EDA- or LPS-induced IL-8, IL-6, COX2, MMP1, and PGE2 expression in primary human amnion mesenchymal cells. Our data suggest that both econazole nitrate and parthenolide would be the promising compounds which can prevent preterm labor via inhibition of fNA-EDA-TLR4 interaction.

Academic Significance and Societal Importance of the Research Achievements

早産の病態生理に鑑みれば、TLR4を阻害するアプローチは合理的かつ効果的であるが、これまでにこの方法を用いた早産治療の研究は存在しなかった。我々がヒト羊膜での有力なTLR4阻害化合物を同定し、その効果を確認できた学術的意義は大きい。またTLR4を有効に阻害する化合物は、重症感染症や敗血症性ショックといったTLR4を介する別の重篤な疾患の治療への応用の可能性があり、社会的意義も大きい。