title: Nafamostat Mesilate Improves Neurological Outcome and Axonal Regeneration after Stroke in Rats.
abstract: Disability including deficiency in sensorimotor and cognition functions is a dominant consequence after stroke. Evidence suggests that serine proteases play an important role in the physiology and pathology of the brain. Previous studies reported that nafamostat mesilate (NM), a synthetic serine protease inhibitor, attenuates neuronal damage in the acute phase after stroke. However, its efficacy in the chronic phase and the mechanism underlying its beneficial effect are not fully known. Here, we have studied whether NM improves long-term functional recovery after ischemic stroke. Experimental ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAO). NM treatment attenuated the brain infarct volume and the loss of body weight and improved the recovery of sensorimotor and cognitive functions. One month after tMCAO, neuronal axons and dendrites were preserved in the NM group, accompanied by increasedsynaptic proteins and structures in the ipsilateral hippocampus. The expression of brain-derived neurotrophic factor, nerve growth factor and neurotrophin-3 was increased in the contralateral sensorimotor cortex and ipsilateral hippocampus by the administration of NM. Furthermore, NM activated tyrosine receptor kinase B (TrkB), extracellular signal-regulated kinas1/2(ERK1/2) and cAMP-response element binding protein (CREB) and inhibited the activity of Cyclin-dependent Kinase 5 (Cdk5) in the contralateral sensorimotor cortex and ipsilateral hippocampus. These results demonstrated that NM treatment could improve neurological outcome and axonal regeneration, which might be correlated with down-regulating Cdk5 activity and up-regulating TrkB-ERK1/2-CREB pathway.
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: 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: Hao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing, 210009, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Tao
authors.affiliation: School of Pharmacology and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia. 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. hliao@cpu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology*; D001550:Benzamidines; D001835:Body Weight / Q000187:drug effects; D020520:Brain Infarction / Q000150:complications / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D008297:Male; D008959:Models, Neurological; D009414:Nerve Growth Factors / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D001550:Benzamidines; D017362:Cyclic AMP Response Element-Binding Protein; D006146:Guanidines; D009414:Nerve Growth Factors; D020813:Receptor, trkB; D051360:Cyclin-Dependent Kinase 5; D048049:Extracellular Signal-Regulated MAP Kinases; C032855:nafamostat
keywords: Brain ischemia; Functional recovery; Nafamostat mesilate