title: PAR-1 deficiency protects against neuronal damage and neurologic deficits after unilateral cerebral hypoxia/ischemia.
abstract: Cardiovascular and neurologic surgeries often involve a temporary reduction in cerebral blood flow. In these conditions, as well as during cerebral ischemia and traumatic brain injury, the temporary loss of oxygen and glucose initiates a cascade of cellular events that culminate in neuronal death and damage. Understanding the mechanisms that contribute to neuronal death after hypoxia/ischemia is critically important for treatment of such brain injury. Here, we use a model of combined cerebral hypoxia/ischemia (H/I) to examine the role of protease-activated receptor-1 (PAR-1) in hypoxic/ischemic neuronal damage. Our data show that PAR-1-deficient mice have smaller lesion volumes than wild-type controls after 45 minutes of H/I. The results of the genetic block of PAR-1 were corroborated using a PAR-1 antagonist, which decreased infarct volume in wild-type C57Bl6 mice. Examination of cellular responses to H/I reveals that PAR-1 -/- animals have less cellular death and diminished glial fibrillary acidic protein expression. Additionally, PAR-1 -/- mice exhibit less motor behavior impairment in rotorod and inverted wire-hang tests. These data suggest that PAR-1 contributes to hypoxic/ischemic brain injury and are consistent with other studies that implicate serine proteases and their receptors in neuropathology after cerebral insults.
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Olson
authors.forename: Polina
authors.initials: P
authors.lastname: Lyuboslavsky
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.forename: Robert J
authors.initials: RJ
authors.lastname: McKeon
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D016923:Cell Death / Q000502:physiology; D007839:Functional Laterality; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000503:physiopathology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D044463:Receptor, PAR-1 / Q000172:deficiency*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D044463:Receptor, PAR-1