title: Nafamostat mesilate attenuates transient focal ischemia/reperfusion-induced brain injury via the inhibition of endoplasmic reticulum stress.
abstract: Nafamostat mesilate (NM), a serine protease inhibitor, has a broad range of clinical applications that include use as an anticoagulant during hemodialysis in cerebral hemorrhage patients, as a hemoperfusion anticoagulant for patients with intravascular coagulation, hemorrhagic lesions, and hemorrhagic tendencies, and for the improvement of acute pancreatitis. However, the effects of NM on acute cerebral ischemia have yet to be investigated. Thus, the present study utilized a rat model in which transient middle cerebral artery occlusion (MCAO) was used to induce ischemic injury to investigate the effects of NM on infarct volume and histological and biological changes. NM (1mg/kg) was intravenously administered prior to and after the MCAO procedure. Compared to control rats, the administration of NM significantly decreased infarct size and the extent of brain edema after the induction of focal ischemia via MCAO. Additionally, NM treatment attenuated MCAO-induced neuronal degeneration and activation of microglia and astrocytes. NM treatment also inhibited the MCAO-induced expression levels of glucose-regulated protein 78 (GRP78), CATT/EBP homologous protein (CHOP), and p-eukaryotic initiation factor 2α (eIF2α), which are endoplasmic reticulum (ER) stress markers, in the cerebral cortex. The present findings demonstrate that NM exerts neuroprotective effects in the brain following focal ischemia via, at least in part, the inhibition of ER stress.
authors.affiliation: Department of physiology, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Sun Kwan
authors.initials: SK
authors.lastname: Kwon
authors.affiliation: Department of Surgery, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Moonsang
authors.initials: M
authors.lastname: Ahn
authors.affiliation: Department of Neurology, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea.
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Song
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Shin Kwang
authors.initials: SK
authors.lastname: Kang
authors.affiliation: Department of Endocrinology, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Saet-Byel
authors.initials: SB
authors.lastname: Jung
authors.affiliation: Department of physiology, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Nagar
authors.initials: N
authors.lastname: Harsha
authors.affiliation: Department of Rehabilitation Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea.
authors.forename: Sungju
authors.initials: S
authors.lastname: Jee
authors.affiliation: Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Moon
authors.affiliation: Department of Pathology, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Kwang-Sun
authors.initials: KS
authors.lastname: Suh
authors.affiliation: Department of physiology, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Sang Do
authors.initials: SD
authors.lastname: Lee
authors.affiliation: Department of physiology, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Byeong Hwa
authors.initials: BH
authors.lastname: Jeon
authors.affiliation: Department of Anatomy, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea. Electronic address: visnu528@cnu.ac.kr.
authors.forename: Dong Woon
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of physiology, School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea. Electronic address: cskim@cnu.ac.kr.
authors.forename: Cuk-Seong
authors.initials: CS
authors.lastname: Kim
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001550:Benzamidines; D001929:Brain Edema / Q000188:drug therapy; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005452:Fluoresceins; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use*; D006360:Heat-Shock Proteins / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009460:Neurologic Examination; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D051742:Transcription Factor CHOP / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001550:Benzamidines; D015852:Eukaryotic Initiation Factor-2; D005452:Fluoresceins; D006146:Guanidines; D006360:Heat-Shock Proteins; D051742:Transcription Factor CHOP; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C435731:fluoro jade; C032855:nafamostat
keywords: Cerebral ischemia; ER stress; MCAO; Nafamostat mesilate