title: PAR-1 antagonist SCH79797 ameliorates apoptosis following surgical brain injury through inhibition of ASK1-JNK in rats.
abstract: Neurosurgical procedures inevitably produce intraoperative hemorrhage. The subsequent entry of blood into the brain parenchyma results in the release of large amounts of thrombin, a known contributor to perihematomal edema formation and apoptosis after brain injury. The present study seeks to test 1) the effect of surgically induced brain injury (SBI) on thrombin activity, expression of thrombin's receptor PAR-1, and PAR-1 mediated apoptosis; 2) the effect of thrombin inhibition by argatroban and PAR-1 inhibition by SCH79797 on the development of secondary brain injury in the SBI model on rats. A total of 88 Sprague-Dawley male rats were randomly divided into sham, vehicle-, argatroban-, or SCH79797-treated groups. SBI involved partial resection of the right frontal lobe under inhalation isoflurane anesthesia. Sham-operated animals received only craniotomy. Thrombin activity, brain water content, and neurological deficits were measured at 24 h following SBI. Involvement of the Ask1/JNK pathway in PAR-1-induced post-SBI apoptosis was characterized by using Ask1 or JNK inhibitors. We observed that SBI increased thrombin activity, yet failed to demonstrate any effect on PAR-1 expression. Argatroban and SCH79797 reduced SBI-induced brain edema and neurological deficits in a dose-dependent manner. SBI-induced apoptosis seemed mediated by the PAR-1/Ask1/JNK pathways. Administration of SCH79797 ameliorated the apoptosis following SBI. Our findings indicate that PAR-1 antagonist protects against secondary brain injury after SBI by decreasing both brain edema and apoptosis by inactivating PAR-1/Ask1/JNK pathway. The anti-apoptotic effect of PAR-1 antagonists may provide a promising path for therapy following SBI.
authors.affiliation: Department of Basic Sciences, Loma Linda University, Loma Linda, California, USA. amanaenko@llu.edu
authors.forename: Anatol
authors.initials: A
authors.lastname: Manaenko
authors.forename: Xuejun
authors.initials: X
authors.lastname: Sun
authors.forename: Cherine H
authors.initials: CH
authors.lastname: Kim
authors.forename: Junhao
authors.initials: J
authors.lastname: Yan
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Ma
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000601:surgery; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism*; D007150:Immunohistochemistry; D007431:Intraoperative Complications / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors; D008297:Male; D019635:Neurosurgical Procedures / Q000009:adverse effects*; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors
chemical_list: C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011758:Pyrroles; D011799:Quinazolines; D048848:MAP Kinase Kinase Kinase 5; D048670:MAP Kinase Kinase 4; D013917:Thrombin; D010975:Platelet Aggregation Inhibitors