PT  - JOURNAL ARTICLE
AU  - Seung-Woo Kim
AU  - Hyun Ji Kim
AU  - Joo-Hyun Shin
AU  - Il-Doo Kim
AU  - Jung-Eun Lee
AU  - Pyung-Lim Han
AU  - Sung-Wha Yoon
AU  - Ja-Kyeong Lee
TI  - Robust protective effects of a novel multi-modal neuroprotectant OBA-09 (a salicylic acid/pyruvate ester) in the postischemic brain
AID  - 10.1124/mol.110.067520
DP  - 2010 Oct 29
TA  - Molecular Pharmacology
PG  - mol.110.067520
4099  - http://molpharm.aspetjournals.org/content/early/2010/10/29/mol.110.067520.short
4100  - http://molpharm.aspetjournals.org/content/early/2010/10/29/mol.110.067520.full
AB  - Cerebral ischemia leads to brain injury via a complex series of pathophysiological events. Therefore, multi-drug treatments or multi-targeting drug treatments are attractive options in efficiently limiting brain damage. Here, we report a novel multi-functional 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 anti-oxidative effects in the postischemic brain, which was evidenced by remarkable reduction of lipid peroxidation and 4-hydroxy-2-nonenal (HNE) staining in OBA-09-administered animals. ROS 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 (HPLC) 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 anti-oxidative function of OBA-09 is executed by itself and also by salicylic acid after the hydrolysis. In addition to anti-oxidative function, OBA-09 exerts anti-excitotoxic and anti-Zn2+-toxic functions, which might be attributed to attenuation of ATP and nicotinamide adenine dinucleotide (NAD) depletion and to suppression of NF-κB activity induction. Together these results indicate that OBA-09 has a potent therapeutic potential as a multi-modal neuroprotectant in the postischemic brain and these effects were conferred by OBA-09 itself and subsequently its hydrolyzed products.