Robust neuroprotective effects of 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid (OPTBA), a HTB/pyruvate ester, in the postischemic rat brain

摘要

Postischemic brain damage in stroke is proceded with complicated pathological events, and so multimodal drug treatments may offer better therapeutic means for improving clinical outcomes. Here, we report robust neuroprotective effects of a novel compound, 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid (OPTBA), a 2-hydroxy-4-trifluoromethyl benzoic acid (HTB, a metabolite of triflusal)-pyruvate ester. Intravenous administration of OPTBA (5?mg/kg) 3 or 6?h after middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats reduced infarct volumes to 38.5?±?11.4% and 46.5?±?15.3%, respectively, of that of MCAO controls, and ameliorated motor impairment and neurological deficits. Importantly, neuroprotective effects of OPTBA were far greater than those afforded by combined treatment of HTB and pyruvate. Furthermore, OPTBA suppressed microglial activation and proinflammatory cytokine inductions more effectively than HTB/pyruvate co-treatment in the postischemic brain and LPS-treated cortical slice cultures and also attenuated NMDA-induced neuronal death in hippocampal slice cultures. LC-MS analysis demonstrated that OPTBA was hydrolyzed to HTB and pyruvate with a t1/2 of 38.6?min in blood and 7.2 and 2.4?h in cortex and striatum, respectively, and HTB was maintained for more than 24?h both in blood and brain tissue. Together these results indicate OPTBA acts directly and via its hydrolysis products, thus acting as a multimodal neuroprotectant in the postischemic brain.