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

Abstract

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.

PET Imaging of Serotoninergic Neurotransmission with [11C]DASB and [18F]altanserin after Focal Cerebral Ischemia in Rats

“…7 Moreover, the modulation of serotoninergic neurotransmission by using selective serotonin reuptake inhibitors such as fluoxetine and citalopram improved motor and cognitive recovery in both the clinic 8,9 and the laboratory. 10 Positron emission tomography (PET) with [ 11 C]DASB and [ 18 F]altanserin has widely been used to investigate the availability of serotonin transporter (SERT) and serotonin receptor 5-HT 2A in both humans and animals. [11][12][13][14] This imaging method has proven to be helpful in elucidating the role of serotoninergic mechanisms in aging, 15 and neurologic and psychiatric pathologies such as Alzheimer's disease, 16 depression 17,18 obsessive-compulsive disorder, 19 bipolar disorder, 20 and schizophrenia.…”

Paroxetine Prevents Loss of Nigrostriatal Dopaminergic Neurons by Inhibiting Brain Inflammation and Oxidative Stress in an Experimental Model of Parkinson’s Disease

“…The most frequent neuropsychiatric symptom in PD is depression (11), and several clinical reports have shown that paroxetine is safe and effective in treating PD-associated depression (12,13). Antidepressants such as fluoxetine and imipramine have been shown to possess potent antiinflammatory effects in the rat cerebral ischemia model of middle cerebral artery occlusion (14) and in a mouse model of Alzheimer's disease (15). These studies demonstrated that fluoxetine and/or imipramine attenuated expression of TNF-a and IL-1b.…”

Effect of Fluoxetine on Motor Recovery after Acute Haemorrhagic Stroke: A Randomized Trial

“…In animals, there may be several mechanisms for neuroprotective effects of SSRIs, such as reducing inflammation (e.g. repression of microglia activation) [32] and by enhancement of specific protein expression (hypoxia inducible factor-1 alpha) [33]. Third, SSRIs can indirectly affect an important hormonal system in the body, the adrenergic system, through up-regulation of beta1 receptors [34].…”