title: Fluoxetine inhibits transient global ischemia-induced hippocampal neuronal death and memory impairment by preventing blood-brain barrier disruption.
abstract: 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.
authors: Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: Jee Y
authors: JY
authors: Lee
authors: Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: Hyung E
authors: HE
authors: Lee
authors: Graduate Program for Neuroscience, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: So R
authors: SR
authors: Kang
authors: Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: Hye Y
authors: HY
authors: Choi
authors: Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address: jhryu63@khu.ac.kr.
authors: Jong H
authors: JH
authors: Ryu
authors: Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; Graduate Program for Neuroscience, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address: tyune@khu.ac.kr.
authors: Tae Y
authors: TY
authors: Yune
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007797:Laminin / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008815:Mice, Inbred Strains; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D062793:Occludin / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D007797:Laminin; D018696:Neuroprotective Agents; D062793:Occludin; C568986:Ocln protein, mouse; D012333:RNA, Messenger; D005473:Fluoxetine; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Blood–spinal cord barrier; Global ischemia; Hippocampus; Matrix metalloprotease; Tight junction