title: Anti-inflammatory and anti-excitoxic effects of diethyl oxopropanamide, an ethyl pyruvate bioisoster, exert robust neuroprotective effects in the postischemic brain.
abstract: Ethyl pyruvate (EP) is a simple aliphatic ester of pyruvic acid and has been shown to have robust neuroprotective effects via its anti-inflammatory, anti-oxidative, and anti-apoptotic functions. In an effort to develop novel EP derivatives with greater protective potencies than EP, we generated four EP isosteres, among them the neuroprotective potency of N,N-diethyl-2-oxopropanamide (DEOPA), in which the ethoxy group of EP was replaced with diethylamine, was far greater than that of EP. When DEOPA was administered intravenously (5 mg/kg) to rat middle cerebral artery occlusion (MCAO) model at 6 hrs post-surgery, it suppressed infarct formation, ameliorated neurological and sensory/motor deficits, and inhibited microglial activation and neutrophil infiltrations in the postischemic brain more effectively than EP. In particular, DEOPA markedly suppressed LPS-induced nitrite production and cytokine/chemokine inductions in microglia, neutrophils, and endothelial cells and these effects are attributable to inhibition of the activity of NF-κB by suppressing IκB-α degradation and p65 to DNA binding. In addition, DEOPA suppressed NMDA-induced neuronal cell death in primary cortical neuron cultures by NAD replenishment and suppression of NF-κB activity. Together, these results indicate DEOPA has multi-modal protective effects against ischemic brain damage targeting numerous cell types in the brain and also against other inflammation-related diseases.
authors.affiliation: Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea.|Medical Research Center, Inha University School of Medicine, Inchon, Republic of Korea.
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea.|Medical Research Center, Inha University School of Medicine, Inchon, Republic of Korea.
authors.forename: Il-Doo
authors.initials: ID
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea.|Department of Biomedical Sciences, Inha University School of Medicine, Inchon, Republic of Korea.
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea.|Medical Research Center, Inha University School of Medicine, Inchon, Republic of Korea.
authors.forename: Hahnbie
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.
authors.forename: Sung-Hwa
authors.initials: SH
authors.lastname: Yoon
authors.affiliation: Department of Anatomy, Inha University School of Medicine, Inchon, Republic of Korea.|Medical Research Center, Inha University School of Medicine, Inchon, Republic of Korea.
authors.forename: Ja-Kyeong
authors.initials: JK
authors.lastname: Lee
mesh_terms: D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy / Q000209:etiology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051996:Transcription Factor RelA / Q000737:chemistry / Q000378:metabolism
chemical_list: D000577:Amides; D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D018696:Neuroprotective Agents; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide