期刊
NEUROPHARMACOLOGY
卷 79, 期 -, 页码 161-171出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2013.11.011
关键词
Blood-spinal cord barrier; Matrix metalloprotease; Global ischemia; Tight junction; Hippocampus
资金
- National Research Foundation of Korea
- Ministry of Science, ICT & Future Planning [2010-0019349, 2008-0061888 (SRC)]
- National Research Foundation of Korea [2010-0019349] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Ischemia induces blood brain barrier (BBB) disruption by matrix metalloproteases (MMPs) activation, leading to neuronal cell death. Here, we show that fluoxetine inhibits apoptotic cell death of hippocampal neuron and memory impairment by blocking BBB disruption after transient global ischemia. Fluoxetine treatment (10 mg/kg) after global ischemia significantly inhibited mRNA expression of MMP-2 and -9 and reduced MMP-9 activity. By Evan blue assay, fluoxetine reduced ischemia-induced BBB permeability. In parallel, fluoxetine significantly attenuated the loss of occludin and laminin in the hippocampal area after ischemia. By immunostaining with occludin antibody, fluoxetine preserved the integrity of vascular networks, especially in hippocampal areas after injury. Fluoxetine also prevented the infiltration of macrophages and inhibited the mRNA expression of inflammatory mediators after injury. In addition, the activation of microglia and astrocyte in hippocampal regions was significantly attenuated by fluoxetine. Finally, fluoxetine reduced apoptotic cell death of hippocampal neurons as well as vascular endothelial cell death and improved learning and memory. Thus, our study suggests that the neuroprotective effect of fluoxetine is likely mediated by blocking MMP activation followed BBB disruption after transient global ischemia, and the drug may represent a potential therapeutic agent for preserving BBB integrity following ischemic brain injury in humans. (C) 2013 Elsevier Ltd. All rights reserved.
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