The synergetic effect of edaravone and borneol in the rat model of ischemic stroke

Eur J Pharmacol. 2014 Oct 5;740:522-31. doi: 10.1016/j.ejphar.2014.06.035. Epub 2014 Jun 27.

Abstract

Free radical production contributes to the early ischemic response and the neuroinflammatory response to injury initiates the second wave of cell death following ischemic stroke. Edaravone is a free radical scavenger, and borneol has shown anti-inflammatory effect. We investigated the synergistic effect of these two drugs in the rat model of transient cerebral ischemia. Edaravone scavenged OH, NO and ONOO─ concentration-dependently, and borneol inhibited ischemia/reperfusion-induced tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) expressions. In the rat model of transient cerebral ischemia and reperfusion, the combination of edaravone and borneol significantly ameliorated ischemic damage with an optimal proportion of 4:1. Emax (% inhibition) of edaravone, borneol and two drugs in combination was 55.7%, 65.8% and 74.3% respectively. ED50 of edaravone and borneol was 7.17 and 0.36 mg/kg respectively. When two drugs in combination, ED50 was 0.484 mg/kg, in which edaravone was 0.387 mg/kg (ineffective dose) and borneol was 0.097 mg/kg (ineffective dose). Combination index (CI)<1 among effects observed in experiments, suggesting a significant synergistic effect. Reduced levels of pro-inflammatory mediators and free radicals were probably associated with the synergistic effect of edaravone and borneol. The combination exhibited a therapeutic time window of 6h in ischemia/reperfusion model, and significantly ameliorated damages in permanent ischemia model. Moreover, two drugs in combination promoted long-term effect, including improved elemental vital signs, sensorimotor functions and spatial cognition. Our results suggest that the combination of edaravone and borneol have a synergistic effect for treating ischemic stroke.

Keywords: Anti-inflammation; Borneol; Cerebral ischemia/reperfusion; Edaravone; Free radical; Synergistic effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Antipyrine / analogs & derivatives*
  • Antipyrine / pharmacology
  • Antipyrine / therapeutic use
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Camphanes / pharmacology
  • Camphanes / therapeutic use*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Cyclooxygenase 2 / metabolism
  • Disease Models, Animal
  • Drug Synergism
  • Drug Therapy, Combination
  • Edaravone
  • Free Radical Scavengers / pharmacology
  • Free Radical Scavengers / therapeutic use*
  • Interleukin-1beta / metabolism
  • Maze Learning / drug effects
  • Neuroglia
  • Neurons / drug effects
  • Rats, Sprague-Dawley
  • Stroke / drug therapy*
  • Stroke / metabolism
  • Stroke / pathology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Inflammatory Agents
  • Camphanes
  • Free Radical Scavengers
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • isoborneol
  • Edaravone
  • Antipyrine