title: Impaired fibrinolysis and traumatic brain injury in mice.
abstract: Traumatic brain injury (TBI) has been associated with intravascular coagulation, which may be a result of thromboplastin released following brain injury. Clots thus formed are lysed by plasmin, which is activated by tissue-type and urokinase-type plasminogen activators (uPA). To evaluate the association between traumatic intravascular coagulation and post-traumatic outcome, uPA knockout (uPA-/-) transgenic mice (n=12) or wild-type littermates (WT; n=12) were anesthetized and subjected to controlled cortical impact (CCI) brain injury. A second group of uPA-/- (n=12) and WT mice (n=12) were subjected to sham injury. Motor function was assessed over 2 weeks using the composite neuroscore test and cognition (learning) was assessed with the Morris Water Maze (MWM) at 2 weeks post-injury, whereupon the animals were sacrificed for cortical lesion volume analysis. Motor function was significantly worse in the brain-injured uPA-/- mice when compared to brain-injured WT mice at 48 h (p<0.05) and one week post-injury (p<0.05). These differences resolved by 2 weeks post-injury. There was no significant difference in post-injury cognitive function between uPA-/- mice and WT mice. However, at 2 weeks post-injury, the brain-injured uPA-/- had a significantly larger volume of cortical tissue loss than their WT counterparts (p<0.05). These results demonstrate that the absence of uPA in mice aggravates acute motor deficit and exacerbates cortical tissue loss following CCI brain injury, and suggests a neuroprotective role of the fibrinolytic process following TBI.
authors.affiliation: Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania School of Medicine, and Veterans Administrations Medical Center, Philadelphia, Pennsylvania 19106, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Morales
authors.forename: Tracy
authors.initials: T
authors.lastname: McIntosh
authors.forename: Valeria
authors.initials: V
authors.lastname: Conte
authors.forename: Scott
authors.initials: S
authors.lastname: Fujimoto
authors.forename: David
authors.initials: D
authors.lastname: Graham
authors.forename: M Sean
authors.initials: MS
authors.lastname: Grady
authors.forename: Sherman C
authors.initials: SC
authors.lastname: Stein
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000473:pathology* / Q000523:psychology; D003071:Cognition / Q000502:physiology; D005260:Female; D005342:Fibrinolysis / Q000502:physiology*; D007839:Functional Laterality / Q000502:physiology; D007150:Immunohistochemistry; D020767:Intracranial Thrombosis / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
chemical_list: D014568:Urokinase-Type Plasminogen Activator