title: Probenecid protects against cerebral ischemia/reperfusion injury by inhibiting lysosomal and inflammatory damage in rats.
abstract: Probenecid has been used for decades to treat gout, and recent studies have revealed it is also a specific inhibitor of the pannexin-1 channel. It has been reported that the pannexin-1 channel is involved in ischemic injury. Here, we investigated the neuroprotective effect and the possible mechanisms of action of probenecid in global cerebral ischemia/reperfusion (I/R) injury in rats. Twenty minutes of transient global cerebral I/R injury was induced using the four-vessel occlusion (4-VO) method in male Sprague-Dawley rats. Different doses of probenecid were administered intravenously, intraperitoneally, or by gavage before or after reperfusion. Probenecid via all three routes protected against CA1 neuronal death when given before reperfusion. This protective effect continued when probenecid was given at 2h after reperfusion, but not at 6h. Interestingly, the protective effect regained if probenecid was given continuously for 7days after reperfusion. The release of cathepsin B and overexpression of calpain-1 after reperfusion were inhibited, while the upregulation of Hsp70 was strengthened by probenecid pre-treatment. Furthermore, the activation and proliferation of microglia and astrocytes after I/R injury were suppressed by continuous given for 7days, but only partly by a single dose at 6h of reperfusion. Thus, our data indicate that probenecid protects against transient global cerebral I/R injury probably by inhibiting calpain-cathepsin pathway and the inflammatory reaction.
authors.affiliation: The Brain Medical Center and the Collaborative Innovation Center for Brain Science, Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
authors.forename: R
authors.initials: R
authors.lastname: Wei
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Brain Medical Center and the Collaborative Innovation Center for Brain Science, Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Neurology, Renmin Hospital, Wuhan University, Wuhan 430000, China.
authors.forename: B
authors.initials: B
authors.lastname: Yin
authors.affiliation: The Brain Medical Center and the Collaborative Innovation Center for Brain Science, Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
authors.forename: F
authors.initials: F
authors.lastname: He
authors.affiliation: The Brain Medical Center and the Collaborative Innovation Center for Brain Science, Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Du
authors.affiliation: The Brain Medical Center and the Collaborative Innovation Center for Brain Science, Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
authors.forename: G
authors.initials: G
authors.lastname: Peng
authors.affiliation: The Brain Medical Center and the Collaborative Innovation Center for Brain Science, Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address: luobenyan@zju.edu.cn.
authors.forename: B
authors.initials: B
authors.lastname: Luo
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004660:Encephalitis / Q000378:metabolism / Q000517:prevention & control; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011339:Probenecid / Q000008:administration & dosage*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D000096985:Calponins
chemical_list: D002135:Calcium-Binding Proteins; D002401:Cathepsin B; D018840:HSP70 Heat-Shock Proteins; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D011339:Probenecid; D000096985:Calponins
keywords: calpain-1; cathepsin B; cerebral ischemia/reperfusion injury; heat shock protein 70; inflammation; probenecid