Anti-inflammatory and anti-excitoxic effects of diethyl oxopropanamide, an ethyl pyruvate bioisoster, exert robust neuroprotective effects in the postischemic brain

作者：Lee, Hye-Kyung; Kim, Il-Doo; Kim, Seung-Woo; Lee, Hahnbie; Park, Ju-Young; Yoon, Sung-Hwa^*; Lee, Ja-Kyeong^*

来源：Scientific Reports, 2017, 7(1): 1-14.

DOI：10.1038/srep42891

• FACTOR-KAPPA-B
• WIDE THERAPEUTIC WINDOW
• IN-VITRO
• ACTIVATED MICROGLIA
• HUMAN-NEUTROPHILS
• ISCHEMIC-INJURY
• P-SELECTIN
• CELLS
• RAT
• EXPRESSION

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-kappa B by suppressing I kappa B-alpha 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-kappa B 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.

• 出版日期2017-2-21