title: Suppression of ischaemia-induced injuries in rat brain by protease-activated receptor-1 (PAR-1) activating peptide.
abstract: Ischaemic stroke has become one of the leading causes of death and disability worldwide. The role of protease activated receptor-1 (PAR-1) in this disease is uncertain. In the present study, the actions of a protease activated receptor-1 activating peptide (PAR-1 AP) SFLLRN-NH2 were investigated in an in vivo rat model of ischaemic stroke induced by middle cerebral artery occlusion (MCAO) and in an in vitro model induced by oxygen and glucose deprivation (OGD) in primary cultured rat embryonic cortical neurones. Rats subjected to MCAO exhibited increased brain infarct volume, oedema, and neurological deficit. Rat cortical neurones subjected to OGD showed increased lactate dehydrogenase, caspase-3 activity and TUNEL positive cells, whereas, mitochondrial membrane potential and cell viability were decreased. Furthermore, both models had elevated levels of reactive oxygen species, nitrite, and malondialdehyde, while anti-oxidant enzymes and bcl-2/bax ratio were decreased. These detrimental changes were suppressed by SFLLRN-NH2, and its protective actions were inhibited by a PAR-1 antagonist (BMS-200261). In summary, SFLLRN-NH2 was found to possess anti-oxidant and anti-apoptotic properties, and it produced marked inhibition on the detrimental effects of ischaemia in in vivo and in vitro models of ischaemic stroke. The present findings suggest PAR-1 is a promising target for development of novel treatments of ischaemic brain disease.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; Pharmacy Department, Beijing Shijitan Hospital, Capital Medical University, Haidian District, Beijing, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhen
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Ethel Sau Kuen
authors.initials: ESK
authors.lastname: Ng
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. Electronic address: francislam@cuhk.edu.hk.
authors.forename: Francis Fu Yuen
authors.initials: FFY
authors.lastname: Lam
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009573:Nitrites / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism; D020521:Stroke / Q000150:complications; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000975:Antioxidants; D009573:Nitrites; D009842:Oligopeptides; C462999:PAR-1-activating peptide; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D044463:Receptor, PAR-1; D051028:bcl-2-Associated X Protein; D008315:Malondialdehyde
keywords: Anti-oxidant; Apoptosis; Middle cerebral artery occlusion; Oxygen glucose deprivation; Protease activated receptor; Stroke