Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect

J Neurosci Res. 2009 Mar;87(4):1037-45. doi: 10.1002/jnr.21899.


Fluoxetine is a selective serotonin reuptake inhibitor that is widely used in the treatment of major depression including after stroke. In this study, we tested whether fluoxetine protects neuronal death in a rat cerebral ischemia model of middle cerebral artery occlusion (MCAO). The administration of fluoxetine intravenously (10 mg/kg) at 30 min, 3 hr, or 6 hr after MCAO reduced infarct volumes to 21.2+/-6.7%, 14.5+/-3.0%, and 22.8+/-2.9%, respectively, of that of the untreated control. Moreover, the neuroprotective effect of fluoxetine was evident when it was administered as late as 9 hr after MCAO/reperfusion. These neuroprotective effects were accompanied by improvement of motor impairment and neurological deficits. The fluoxetine-treated brain was found to show marked repressions of microglia activation, neutrophil infiltration, and proinflammatory marker expressions. Moreover, fluoxetine suppressed NF-kappaB activity dose-dependently in the postischemic brain and also in lipopolysaccharide-treated primary microglia and neutrophil cultures, suggesting that NF-kappaB activity inhibition explains in part its anti-inflammatory effect. These results demonstrate that curative treatment of fluoxetine affords strong protection against delayed cerebral ischemic injury, and that these neuroprotective effects might be associated with its anti-inflammatory effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Biomarkers / metabolism
  • Cells, Cultured
  • Cognition Disorders / drug therapy
  • Dose-Response Relationship, Drug
  • Fluoxetine / therapeutic use*
  • Infarction, Middle Cerebral Artery / drug therapy*
  • Infarction, Middle Cerebral Artery / immunology
  • Infarction, Middle Cerebral Artery / physiopathology
  • Lipopolysaccharides / pharmacology
  • Male
  • Microglia / drug effects
  • Microglia / physiology
  • Motor Activity / drug effects
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Neuroprotective Agents / therapeutic use*
  • Neutrophils / drug effects
  • Neutrophils / physiology
  • Rats
  • Rats, Sprague-Dawley


  • Anti-Inflammatory Agents, Non-Steroidal
  • Biomarkers
  • Lipopolysaccharides
  • NF-kappa B
  • Neuroprotective Agents
  • Fluoxetine