Journal Article

Fluoxetine attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage: a possible role for the regulation of TLR4/MyD88/NF-κB signaling pathway

Ruan, Wu, Cai, Jing, Li, Jian-ru, Chen, Jing-sen, Liu, Fu-yi, Guan, Guo-ping, Pan, Hai-zhou, Qian, Cong, Wang, Lin, Chen, Gao, Wang, Chun

2018

Overview

Background Neuroinflammation is closely associated with functional outcome in subarachnoid hemorrhage (SAH) patients. Our recent study demonstrated that fluoxetine inhibited NLRP3 inflammasome activation and attenuated necrotic cell death in early brain injury after SAH, while the effects and potential mechanisms of fluoxetine on neuroinflammation after SAH have not been well-studied yet. Methods One hundred and fifty-three male SD rats were subjected to the endovascular perforation model of SAH. Fluoxetine (10 mg/kg) was administered intravenously at 6 h after SAH induction. TAK-242 (1.5 mg/kg), an exogenous TLR4 antagonist, was injected intraperitoneally 1 h after SAH. SAH grade, neurological scores, brain water content, Evans blue extravasation, immunofluorescence/TUNEL staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot were performed. Results Fluoxetine administration attenuated BBB disruption, brain edema, and improved neurological function after SAH. In addition, fluoxetine alleviated the number of Iba-1-positive microglia/macrophages, neutrophil infiltration, and cell death. Moreover, fluoxetine reduced the levels of pro-inflammatory cytokines, downregulated the expression of TLR4 and MyD88, and promoted the nuclear translocation of NF-κB p65, which were also found in rats with TAK-242 administration. Combined administration of fluoxetine and TAK-242 did not enhance the neuroprotective effects of fluoxetine. Conclusion Fluoxetine attenuated neuroinflammation and improved neurological function in SAH rats. The potential mechanisms involved, at least in part, TLR4/MyD88/NF-κB signaling pathway.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Aneurysms / Animals / Apoptosis / Biomedical and Life Sciences / Biomedicine / Blood-brain barrier / Blood-Brain Barrier - drug effects / Blood-Brain Barrier - physiopathology / Brain Edema - drug therapy / Brain Edema - etiology / Brain Injuries - drug therapy / Brain Injuries - etiology / Brain Injuries - mortality / Brain Injuries - pathology / Brain injury / Calcium-Binding Proteins - metabolism / Cardiovascular system / Carotid arteries / Cell activation / Cell death / Cytokines / Cytokines - genetics / Cytokines - metabolism / Diabetes / Disease Models, Animal / Early brain injury / Edema / Extravasation / Fluoxetine / Fluoxetine - therapeutic use / Gene Expression Regulation - drug effects / Granulocyte Colony-Stimulating Factor - metabolism / Hemorrhage / Immunofluorescence / Immunology / Inflammasomes / Inflammation / Interleukin-3 - metabolism / Ischemia / Laboratory animals / Macrophages / Male / Microfilament Proteins - metabolism / Microglia / MyD88 protein / Myeloid Differentiation Factor 88 - metabolism / Neurobiology / Neuroinflammation / Neurology / Neuroprotection / Neuroprotective Agents - therapeutic use / Neurosciences / NF-kappa B - metabolism / NF-κB protein / Nuclear transport / Polymerase chain reaction / Rats / Rats, Sprague-Dawley / Recombinant Fusion Proteins - metabolism / Rodents / Signal transduction / Signal Transduction - drug effects / Spinal cord / Stroke / Studies / Subarachnoid hemorrhage / Subarachnoid Hemorrhage - complications / Subarachnoid Hemorrhage - mortality / Sulfonamides - therapeutic use / TLR4 protein / Toll-Like Receptor 4 - metabolism / Toll-like receptors / Traumatic brain injury / Tumor necrosis factor-TNF / Water content