Abstract
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.
Highlights
In the postischemic brain, neuronal cell damage and subsequent neurological dysfunction are caused by complicated pathological events occurring in a spatiotemporally-regulated manner
Representative images of infarctions in coronal brain sections are shown (A) and quantitative results are presented as means ±SEMs (n = 5–6) (B). (C,D) OPTBA (1, 2.5, 5, or 10 mg/kg, i.v.) was administered at 6 h after middle cerebral artery occlusion (MCAO)
We showed OPTBA, a HTB-pyruvate ester, exerts a robust neuroprotective effect in the postischemic brain and that this was achieved by its anti-inflammatory and anti-excitotoxic effects probably accomplished directly by OPTBA and by its hydrolysis products, HTB and pyruvate
Summary
Neuronal cell damage and subsequent neurological dysfunction are caused by complicated pathological events occurring in a spatiotemporally-regulated manner. Excitotoxicity and Zn2+ toxicity cause massive neuronal cell damages in the ischemic core during the acute phase[1] and this is followed by inflammation and apoptosis within a few hours to days that exacerbate brain injury[2] It is for this reason that combinatorial or multimodal drug treatments are believed to be most effective for stroke treatment. In addition to its protective effects in the ischemic brain, a study in a transgenic mouse model of Alzheimer’s disease showed that chronic treatment with triflusal reduced dense-cored plaque load and proinflammatory cytokine levels and rescued cognitive deficits[10] It has been reported triflusal inhibited COX-2 expression and PGE2 production in a rat carrageenan-induced air pouch model[11] and that it reduced pro-inflammatory mediators, such as, iNOS, COX-2, and TNF-αafter N-methyl-D-aspartate (NMDA)-induced postnatal excitotoxic damage[12]. We examined hydrolysis kinetics of HTB in serum and brain tissue using LC-MS and investigated molecular mechanisms underlying the neuroprotective effects, in particular, its anti-inflammatory and anti-excitotoxic effects, using hippocampal and cortical slice cultures (Fig. S1)
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