title: Anti-inflammatory effects of OBA-09, a salicylic acid/pyruvate ester, in the postischemic brain.
abstract: Cerebral ischemia leads to brain injury via a complex series of pathophysiological events, and therefore, multi-drug treatments or multi-targeting drug treatments provide attractive options with respect to limiting brain damage. Previously, we reported that a novel multi-functional compound oxopropanoyloxy benzoic acid (OBA-09, a simple ester of pyruvate and salicylic acid) affords robust neuroprotective effects in the postischemic rat brain. OBA-09 exhibited anti-oxidative effects that appeared to be executed by OBA-09 and by the salicylic acid afforded by hydrolysis. Here, we report the anti-inflammatory effects of OBA-09. Microglial activation observed at 2 days post-middle cerebral artery occlusion (MCAO, 90 min) and at 1 day after a LPS injection (0.5 mg/kg, intravenously) in the brains of Sprague-Dawley rats were markedly suppressed by the administration of OBA-09 (10 mg/kg). Inductions of proinflammatory markers (TNF-α, IL-1β, iNOS, and COX-2) were also suppressed by OBA-09 in both the LPS and MCAO models. Moreover, the anti-inflammatory effect of OBA-09 was accompanied by the suppression of infarct formation in the postischemic brain, but appeared to be independent of neuroprotection in LPS-treated rats. The inductions of proinflammatory markers were also inhibited by OBA-09 in LPS-treated BV2 cells (a microglia cell line) and in LPS-treated-primary neutrophils, possibly due to the suppression of NF-κB activity. Interestingly, the anti-inflammatory effect of OBA-09 was greater than that of equivalent co-treatment with pyruvate and salicylic acid. Together these results indicate that OBA-09 is a potent multi-modal neuroprotectant in the postischemic brain, and that its anti-inflammatory effect contributes to its neuroprotective function.
authors.affiliation: Department of Anatomy and Inha Research Institute for Medical Sciences, Inha University School of Medicine, 7-241 Shinheung-dong, Jung-Gu, Inchon 400-712, Republic of Korea.
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Lee
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: Yinchuan
authors.initials: Y
authors.lastname: Jin
authors.forename: Il-Doo
authors.initials: ID
authors.lastname: Kim
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Sung-Hwa
authors.initials: SH
authors.lastname: Yoon
authors.forename: Ja-Kyeong
authors.initials: JK
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011773:Pyruvates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D016328:NF-kappa B; D018696:Neuroprotective Agents; D011773:Pyruvates; D012459:Salicylates; C556030:oxypropanoyloxy benzoic acid
keywords: Anti-inflammation; COX-2; IL-1Β; Iba-1; MCAO; MMP-9; MPO-1; Mac-2; NF-kB; NeuN; OBA-09; Pyruvate; ROS; Salicylic acid; TNF-α; cyclooxygenase-2; iNOS; inducible no synthase; interleukin-1beta; ionized calcium binding adaptor molecule 1; macrophage galactose-specific lectin-2; matrix metalloproteinase-9; middle cerebral artery occlusion; myeloperoxidase-1; neuronal nuclei; nuclear factor kappa-light-chain-enhancer of activated b cells; oxopropanoyloxy benzoic acid; reactive oxygen species; tumor necrosis factor-alpha