Increased expression and activity of urokinase-type plasminogen activator during epileptogenesis.

Our recent large-scale molecular profiling study revealed a sevenfold upregulation in the expression of urokinase-type plasminogen activator (uPA) during epileptogenesis. uPA is a member of the plasminogen activation system, which is a major contributor to the reorganization of neuronal circuits after trauma. Here, we investigated the expression and activity of uPA in normal and epileptogenic rat hippocampus to test a hypothesis that the expression of uPA is altered in brain areas that undergo epilepsy-related circuitry reorganization. Epileptogenesis was triggered by inducing status epilepticus (SE) with electrical stimulation of the amygdala in rats. Continuous video-electroencephalogram recordings were used to monitor the development of SE and the occurrence of spontaneous seizures. Animals were killed at 1, 4 or 14 days after SE, and brains were processed for immunohistochemistry or protein extraction. Confocal microscopy analysis of double-immunolabelled preparations indicated that SE triggered an increased expression of uPA in hippocampal astrocytes, neurons, white matter and blood vessels. Zymography revealed that the expression of uPA protein is associated with increased levels of enzymatically active uPA during epileptogenesis. uPA expression and enzymatic activity peaked within 1-4 days after SE, that is, before the occurrence of spontaneous seizures, and remained elevated for at least 2 weeks. These data suggest that uPA is involved in the reorganization of neuronal tissue during the epileptogenic process.