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Robust protective effects of a novel multimodal neuroprotectant oxopropanoyloxy benzoic acid (a salicylic acid/pyruvate ester) in the postischemic brain
- Robust protective effects of a novel multimodal neuroprotectant oxopropanoyloxy benzoic acid (a salicylic acid/pyruvate ester) in the postischemic brain
- Kim S.-W.; Kim H.J.; Shin J.-H.; Kim I.-D.; Lee J.-E.; Han P.-L.; Yoon S.-H.; Lee J.-K.
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- Molecular Pharmacology
- vol. 79, no. 2, pp. 220 - 228
- SCI; SCIE; SCOPUS
- Cerebral ischemia leads to brain injury via a complex series of pathophysiological events. Therefore, multidrug treatments or multitargeting drug treatments are attractive options in efficiently limiting brain damage. Here, we report a novel multifunctional compound oxopropanoyloxy benzoic acid (OBA-09), a simple ester of pyruvate and salicylic acid. This protective effect was manifested by recoveries from neurological and behavioral deficits. OBA-09 exhibited antioxidative effects in the postischemic brain, which was evidenced by remarkable reduction of lipid peroxidation and 4-hydroxy-2-nonenal staining in OBA-09-administered animals. Reactive oxygen species generation was markedly suppressed in primary cortical cultures under oxygen-glucose deprivation. More interestingly, OBA-09 was capable of scavenging hydroxyl radical in cell-free assays. High-performance liquid chromatography results demonstrated that OBA-09 was hydrolyzed to salicylic acid and pyruvate with t1/2 = 43 min in serum and 4.2 h in brain parenchyma, indicating that antioxidative function of OBA-09 is executed by itself and also by salicylic acid after the hydrolysis. In addition to antioxidative function, OBA-09 exerts anti-excitotoxic and anti-Zn2+-toxic functions, which might be attributed to attenuation of ATP and nicotinamide adenine dinucleotide depletion and to the suppression of nuclear factor-κB activity induction. Together these results indicate that OBA-09 has a potent therapeutic potential as a multimodal neuroprotectant in the postischemic brain and these effects were conferred by OBA-09 itself and subsequently its hydrolyzed products. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics Mol Pharmacol.
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