Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect.
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.
Lim
Chae-Moon
CM
Department of Anatomy, Inha University School of Medicine, Inchon, Korea.
Kim
Seung-Woo
SW
Park
Ju-Young
JY
Kim
Chaekyun
C
Yoon
Sung Hwa
SH
Lee
Ja-Kyeong
JK
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D005473:Fluoxetine