Abstract
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.
- Received August 1, 2010.
- Revision received October 27, 2010.
- Accepted October 28, 2010.
- The American Society for Pharmacology and Experimental Therapeutics