title: Nafamostat mesilate attenuates neuronal damage in a rat model of transient focal cerebral ischemia through thrombin inhibition.
abstract: Evidence suggests that thrombin, a blood coagulation serine protease, mediates neuronal injury in experimental cerebral ischemia. Here, we test the hypothesis that nafamostat mesilate, a serine protease inhibitor, may ameliorate ischemia-induced neuronal damage through thrombin inhibition after ischemic stroke. Focal ischemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery for 2 hours followed by 22 hours of reperfusion. The administration of nafamostat mesilate during ischemia and reperfusion reduced the brain infarct volume, edema volume and neurological deficit. Thrombin expression and activity in the ipsilateral striatum were increased after ischemia, whereas the administration of nafamostat mesilate significantly inhibited thrombin expression and activity. Immunostaining showed that the majority of thrombin was expressed in neurons. TUNEL staining showed that nafamostat mesilate reduced the number of dying cells during ischemia. A rat behavioral test showed that nafamostat mesilate treatment significantly improved the learning ability of ischemic rats. These results suggest that nafamostat mesilate may have a potential therapeutic role for neuroprotection against focal cerebral ischemia through thrombin inhibition.
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, P.R.China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, P.R.China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, P.R.China.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Li
authors.affiliation: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang 212013, P.R.China.
authors.forename: Weining
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, P.R.China.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu D&R Pharmaceutical Co. LTD, Taizhou 225300, P.R.China.
authors.forename: Lufan
authors.initials: L
authors.lastname: An
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, P.R.China.
authors.forename: Tao
authors.initials: T
authors.lastname: Pang
authors.affiliation: School of Science, China Pharmaceutical University, Nanjing 210009, P.R.China.
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Shi
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, P.R.China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage; D001550:Benzamidines; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D006146:Guanidines / Q000008:administration & dosage*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000991:Antithrombins; D001550:Benzamidines; D006146:Guanidines; D018696:Neuroprotective Agents; D013917:Thrombin; D005341:Fibrinolysin; C032855:nafamostat