Epileptogenesis after traumatic brain injury in Plau-deficient mice.

Several components of the urokinase-type plasminogen activator receptor (uPAR)-interactome, including uPAR and its ligand sushi-repeat protein 2, X-linked (SRPX2), are linked to susceptibility to epileptogenesis in animal models and/or humans. Recent evidence indicates that urokinase-type plasminogen activator (uPA), a uPAR ligand with focal proteinase activity in the extracellular matrix, contributes to recovery-enhancing brain plasticity after various epileptogenic insults such as traumatic brain injury (TBI) and status epilepticus. Here, we examined whether deficiency of the uPA-encoding gene Plau augments epileptogenesis after TBI. Traumatic brain injury was induced by controlled cortical impact in the somatosensory cortex of adult male wild-type and Plau-deficient mice. Development of epilepsy and seizure susceptibility were assessed with a 3-week continuous video-electroencephalography monitoring and a pentylenetetrazol test, respectively. Traumatic brain injury-induced cortical or hippocampal pathology did not differ between genotypes. The pentylenetetrazol test revealed increased seizure susceptibility after TBI (p<0.05) in injured mice. Epileptogenesis was not exacerbated, however, in Plau-deficient mice. Taken together, Plau deficiency did not worsen controlled cortical impact-induced brain pathology or epileptogenesis caused by TBI when assessed at chronic timepoints. These data expand previous observations on Plau deficiency in models of status epilepticus and suggest that inhibition of focal extracellular proteinase activity resulting from uPA-uPAR interactions does not modify epileptogenesis after TBI.

Urokinase-type plasminogen activator regulates neurodegeneration and neurogenesis but not vascular changes in the mouse hippocampus after status epilepticus.

Expression of urokinase-type plasminogen activator (uPA) is increased after brain injury, suggesting that, like in cancer tissue, uPA plays roles in brain remodeling. Here we injured brain with intrahippocampal kainic acid (KA) injection in adult Wt and uPA-/- mice. At 20 days post-injury, uPA-/- mice had more severe loss of contralateral pyramidal (p<0.05) and hilar neurons (p<0.05) than Wt mice. The number of doublecortin (DCX)-positive newly born neurons was also reduced in uPA-/- mice as compared to Wt (p<0.01). No difference was observed in granule cell dispersion or distribution of DCX-positive neurons in the dentate gyrus. uPA deficiency did not affect the total length of hippocampal blood vessels or vessel density. No differences were observed in the severity of status epilepticus or consequent epilepsy between the genotypes. These data indicate that uPA deficiency can unfavorably modulate both delayed neurodegeneration and neurogenesis but has little effect on post-injury neuronal migration and vascular density. Our results favor the idea that elevated uPA during the post-injury phase is neuroprotective.