Abstract
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.
Footnotes
This work was supported by the Health Planning Technology and Evaluation Board [Translational Research Grant R05-003000-10562-0].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.067520.
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ABBREVIATIONS:
- OBA-09
- oxopropanoyloxy benzoic acid
- HPLC
- high-performance liquid chromatography
- ROS
- reactive oxygen species
- HNE
- 4-hydroxy-2-nonenal
- MCAO
- middle cerebral artery occlusion
- mNSS
- modified neurological severity score
- TTC
- 2,3,5-triphenyl tetrazolium chloride
- MEM
- minimum essential medium
- DIV
- days in vitro
- OGD
- oxygen-glucose deprivation
- EBSS
- Earle's balanced salt solution
- DCF
- 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate
- MTT
- 3-[4,5-dimethylthiazol-2-yo]-2,5-diphenyltetrazolium bromide
- MDA
- malondialdehyde
- NF-κB
- nuclear factor-κB
- ESI
- electrospray ionization
- MS
- mass spectrometry
- LC
- liquid chromatography
- NMDA
- N-methyl-d-aspartate.
- Received August 1, 2010.
- Accepted October 28, 2010.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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