Combination drug therapy using edaravone and Daio-Orengedoku-to after transient focal ischemia in rats

Methods Find Exp Clin Pharmacol. 2008 Jul-Aug;30(6):443-50. doi: 10.1358/mf.2008.30.6.1241077.


In this study, we investigated the effect of Daio-Orengedoku-to (DOT) on ischemic brain damage in a rat model of focal ischemia-reperfusion and attempted to identify synergistic effects for the combination of edaravone and DOT against ischemic insult. Ischemia was induced by intraluminal occlusion of the right middle cerebral artery for 2 h and reperfusion followed for 22 h. To determine the neuroprotective effect of DOT, it was administered orally just before reperfusion and then 2 h after reperfusion. To examine the effects of combination therapy on survival, rats were divided into groups treated with edaravone, DOT, and edaravone and DOT. Microglial activation, neutrophil infiltration and brain-derived neurotrophic factor (BDNF) expression were examined in surviving animals. Infarct volume was significantly reduced by DOT (100, 200 and 400 mg/kg; P < 0.05), and edaravone plus DOT markedly improved the survival rate after transient ischemia (P = 0.0133). Microglial activation was reduced by edaravone and DOT and their combination (P < 0.05), and neutrophil infiltration was lowered in these groups (P < 0.05). BDNF-positive cells were increased in the combination edaravone and DOT group (P < 0.05). It appears that the neuroprotective mechanisms of combined therapy involve inhibition of microglial activation, reduction of invading neutrophils and enhancement of BDNF expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipyrine / analogs & derivatives*
  • Antipyrine / therapeutic use
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Drug Therapy, Combination
  • Drugs, Chinese Herbal / therapeutic use*
  • Edaravone
  • Free Radical Scavengers / therapeutic use*
  • Immunohistochemistry
  • Infarction, Middle Cerebral Artery / drug therapy
  • Infarction, Middle Cerebral Artery / pathology
  • Ischemic Attack, Transient / drug therapy*
  • Male
  • Microglia / drug effects
  • Neuroprotective Agents*
  • Neutrophil Infiltration / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / psychology


  • Brain-Derived Neurotrophic Factor
  • Drugs, Chinese Herbal
  • Free Radical Scavengers
  • Neuroprotective Agents
  • oren gedoku to
  • Edaravone
  • Antipyrine