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.

Epileptogenesis after traumatic brain injury in Plau-deficient mice

“…In the present study, however, the lesion volume, ratio of ipsilateral to contralateral cortical volumes, and the rostrocaudal extent of the cortical lesion at 6 or 8 months post-CCI were similar between genotypes. Thus, our findings did not confirm previous observations of a neuroprotective effect of uPA in a kainate-induced SE model [42] or CCI TBI model [26]. The differences in the findings could relate to the type of injury induction (SE vs. TBI).…”

“…Also, the timing of the analysis was different as Morales et al [26] analyzed the data at 2 weeks post-CCI, whereas, our analysis was performed 6 to 8 months post-CCI. Also, while C57BL/6J mice from Jackson Laboratories® were used in both the present and the previous study [26], it is likely that the genetic background of the animals was not identical as they were bought from different vendors at different times, which could affect the findings [44]. Interestingly, Nagai et al [45] reported no difference in infarct size between Plau-deficient and Wt mice at 24 h after focal cerebral ischemia.…”

“…In adulthood, constitutive expression of uPA in the brain is low, but it can be robustly induced by various types of experimental epileptogenic brain injuries such as status epilepticus (SE), blood-brain barrier damage, and hypoxic-ischemic injury [20][21][22]. Functional studies in experimental models revealed that a deficiency in Plau, a gene encoding uPA, is associated with compromise of both tissue repair and functional outcome after SE and CCI-induced TBI in mice [20][21][22][23][24][25][26].…”

Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) Promote Neurorepair in the Ischemic Brain

“…In summary, these data indicate that the expression of uPA and uPAR increase in the sub-acute, recovery stages of ischemic stroke, and suggest that uPA binding to uPAR plays a central role in the process of neurorepair following an acute ischemic injury. These observations are supported by reports from other groups indicating that uPAR modulates peripheral nerve regeneration after a crush nerve [21] , and that genetic deficiency of uPA aggravates the motor deficit and increases neuronal death in an animal model of traumatic brain injury [26] .…”

Monitoring Functional Impairment and Recovery after Traumatic Brain Injury in Rats by fMRI

“…[17][18][19] The major limitation in patient studies relates to the lack of histological verification of imaging findings. Even though several clinically relevant animal models of TBI are available, 20 studies applying functional imaging after experimental TBI are scarce. A few studies have focused on…”