title: Imatinib preserves blood-brain barrier integrity following experimental subarachnoid hemorrhage in rats.
abstract: Blood-brain barrier (BBB) disruption and consequent edema formation contribute to the development of early brain injury following subarachnoid hemorrhage (SAH). Various cerebrovascular insults result in increased platelet-derived growth factor receptor (PDGFR)-α stimulation, which has been linked to BBB breakdown and edema formation. This study examines whether imatinib, a PDGFR inhibitor, can preserve BBB integrity in a rat endovascular perforation SAH model. Imatinib (40 or 120 mg/kg) or a vehicle was administered intraperitoneally at 1 hr after SAH induction. BBB leakage, brain edema, and neurological deficits were evaluated. Total and phosphorylated protein expressions of PDGFR-α, c-Src, c-Jun N-terminal kinase (JNK), and c-Jun were measured, and enzymatic activities of matrix metalloproteinase (MMP)-2 and MMP-9 were determined in the injured brain. Imatinib treatment significantly ameliorated BBB leakage and edema formation 24 hr after SAH, which was paralleled by improved neurological functions. Decreased brain expressions of phosphorylated PDGFR-α, c-Src, JNK, and c-Jun as well as reduced MMP-9 activities were found in treated animals. PDGFR-α inhibition preserved BBB integrity following experimental SAH; however, the protective mechanisms remain to be elucidated. Targeting PDGFR-α signaling might be advantageous to ameliorate early brain injury following SAH.
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, California, USA.|Department of Neurosurgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Krafft
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Lekic
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Souvenir
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, California, USA.|Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
authors.affiliation: Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D000068877:Imatinib Mesylate; D047468:Immunoprecipitation; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D009460:Neurologic Examination; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D013345:Subarachnoid Hemorrhage / Q000473:pathology*
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D016392:Proto-Oncogene Proteins pp60(c-src); D048670:MAP Kinase Kinase 4
keywords: blood-brain barrier; brain edema rats; imatinib; subarachnoid hemorrhage