Anti-inflammatory effects of OBA-09, a salicylic acid/pyruvate ester, in the postischemic brain

Brain Res. 2013 Aug 28:1528:68-79. doi: 10.1016/j.brainres.2013.06.026. Epub 2013 Jul 11.

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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Brain / drug effects*
  • Brain / pathology
  • Cytokines / metabolism
  • Infarction, Middle Cerebral Artery / metabolism*
  • Infarction, Middle Cerebral Artery / pathology
  • Male
  • Microglia / drug effects
  • NF-kappa B / metabolism
  • Neuroprotective Agents / pharmacology*
  • Pyruvates / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Salicylates / pharmacology*

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • NF-kappa B
  • Neuroprotective Agents
  • Pyruvates
  • Salicylates
  • oxypropanoyloxy benzoic acid