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Anti-Inflammatory and Neuroprotective Effects of DIPOPA (N,N-Diisopropyl-2-Oxopropanamide), an Ethyl Pyruvate Bioisoster, in the Postischemic Brain

  • Hye-Kyung Lee
  • Ju-Young Park
  • Hahnbie Lee
  • Il-Doo Kim
  • Seung-Woo Kim
  • Sung-Hwa YoonEmail author
  • Ja-Kyeong LeeEmail author
Original Article
  • 45 Downloads

Abstract

Ethyl pyruvate (EP) is a simple aliphatic ester of pyruvic acid and has been shown to have protective properties, which have been attributed to its anti-inflammatory, anti-oxidative, and anti-apoptotic functions. In an effort to develop better derivatives of EP, we previously synthesized DEOPA (N,N-diethyl-2-oxopropanamide, a novel isoster of EP) which has greater neuroprotective effects than EP, probably due to its anti-inflammatory and anti-excitotoxic effects. In the present study, we synthesized 3 DEOPA derivatives, in which its diethylamino group was substituted with diisopropylamino, dipropylamino, or diisobutylamino groups. Among them, DIPOPA (N,N-diisopropyl-2-oxopropanamide) containing diisopropylamino group had a greater neuroprotective effect than DEOPA or EP when administered intravenously to a rat middle cerebral artery occlusion (MCAO) model at 9 h after MCAO. Furthermore, DIPOPA had a wider therapeutic window than DEOPA and a marked reduction of infarct volume was accompanied by greater neurological and behavioral improvements. In particular, DIPOPA exerted robust anti-inflammatory effects, as evidenced by marked suppressions of microglia activation and neutrophil infiltration in the MCAO model, in microglial cells, and in neutrophil–endothelial cocultures at lower concentration, and did so more effectively than DEOPA. In particular, DIPOPA remarkably suppressed neutrophil infiltration into brain parenchyma, and this effect was attributed to the expressional inhibitions of cell adhesion molecules in neutrophils of brain parenchyma and in circulating neutrophils via NF-κB inhibition. Together, these results indicate the robust neuroprotective effects of DIPOPA are attributable to its anti-inflammatory effects and suggest that DIPOPA offers a potential therapeutic means of ameliorating cerebral ischemic injury and other inflammation-related pathologies.

Key Words

DIPOPA Stroke Anti-inflammation Ethyl pyruvate NF-κB 

Notes

Acknowledgments

This work was financed by Translational Research Grant (HI17C0342) funded by Korea Health Industry Development Institute (KHIDI) (to J.-K.L.) and Medical Research Center Grant (2014R1A5A2009392) funded by the National Research Foundation (NRF) of Korea (to J.-K.L.).

Compliance with Ethical Standards

All animal studies were carried out in strict accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH, USA 2013) and complied with ARRIVE guidelines (http://www.nc3rs.org/ARRIVE). The animal protocol used in this study was reviewed and approved beforehand by the INHA University-Institutional Animal Care and Use Committee (INHA-IACUC) with respect to ethicality (Approval Number INHA-140522-297).

Supplementary material

13311_2019_711_MOESM1_ESM.docx (992 kb)
ESM 1 (DOCX 991 kb)

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  • Hye-Kyung Lee
    • 1
    • 2
  • Ju-Young Park
    • 3
  • Hahnbie Lee
    • 1
    • 2
  • Il-Doo Kim
    • 1
    • 4
  • Seung-Woo Kim
    • 2
    • 4
  • Sung-Hwa Yoon
    • 3
    Email author
  • Ja-Kyeong Lee
    • 1
    • 2
    Email author
  1. 1.Department of AnatomyInha University School of MedicineInchonRepublic of Korea
  2. 2.Medical Research CenterInha University School of MedicineInchonRepublic of Korea
  3. 3.Department of Molecular Science and TechnologyAjou University School of MedicineSuwonRepublic of Korea
  4. 4.Department of Biomedical SciencesInha University School of MedicineInchonSouth Korea

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