title: Nafamostat mesilate improves function recovery after stroke by inhibiting neuroinflammation in rats.
abstract: Inflammation plays an important role in stroke pathology, making it a promising target for stroke intervention. Nafamostat mesilate (NM), a wide-spectrum serine protease inhibitor, is commonly used for treating inflammatory diseases, such as pancreatitis. However, its effect on neuroinflammation after stroke was unknown. Hence, the effects of NM on the inflammatory response post stroke were characterized. After transient middle cerebral artery occlusion (tMCAO) in rats, NM reduced the infarct size, improved behavioral functions, decreased the expression of proinflammatory mediators (TNF-α, IL-1β, iNOS and COX-2) in a time-dependent manner and promoted the expression of different anti-inflammatory factors (CD206, TGF-β, IL-10 and IL-4) at different time points. Furthermore, NM could inhibit the expression of proinflammatory mediators and promote anti-inflammatory mediators expression in rat primary microglia following exposure to thrombin combined with oxygen-glucose deprivation (OGD). The immune-modulatory effect of NM might be partly due to its inhibition of the NF-κB signaling pathway and inflammasome activation after tMCAO. In addition, NM significantly inhibited the infiltration of macrophage, neutrophil and T lymphocytes, which was partly mediated by the inhibition of monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Taken together, our results indicated that NM can provide long-term protection of the brain against tMCAO by modulating a broad components of the inflammatory response.
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing 210009, China.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Li
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing 210009, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing 210009, China.
authors.forename: Yinquan
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing 210009, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing 210009, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing 210009, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.affiliation: School of Pharmacology and Medical Sciences, University of South Australia, Adelaide, SA 5000, Australia. Electronic address: xin-fu.zhou@unisa.edu.au.
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing 210009, China. Electronic address: hliao@cpu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001550:Benzamidines; D004195:Disease Models, Animal; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D058847:Inflammasomes / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D017628:Microglia / Q000187:drug effects; D016328:NF-kappa B / Q000187:drug effects; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013917:Thrombin / Q000187:drug effects
chemical_list: D001550:Benzamidines; D006146:Guanidines; D058847:Inflammasomes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D015842:Serine Proteinase Inhibitors; D013917:Thrombin; C032855:nafamostat
keywords: Infiltration; Inflammation; Microglia; NF-κB; NLRP3; Nafamostat mesilate; Stroke; Thrombin