Proteolysis of neuronal cell adhesion molecule by the tissue plasminogen activator-plasmin system after kainate...

Tissue plasminogen activator (tPA) is a serine protease that converts inactive plasminogen to the active protease plasmin and mediates extracellular metabolism. tPA is transcriptionally induced in the mouse hippocampus by pharmacological or electrical stimulation of neuronal activity and mediates excitotoxin-induced neuronal degeneration. Therefore, we hypothesized that tPA would be induced in the hippocampus after kainic acid (KA) injection into the lateral cerebral ventricle (LCV) and that the activated tPA-plasmin system would degrade the neuronal cell adhesion molecule (NCAM), which is a component of the extracellular matrix. In order to investigate this possibility, we first examined whether NCAM is a substrate for the tPA plasmin system by incubating mouse brain homogenates with tPA and plasminogen at 37 degrees C. Next, we examined the degradation of NCAM and the changes of tPA activity in the mouse hippocampus with immunohistochemical procedures and histological zymography after KA injection into both LCVs. As a result, we observed neuronal atrophy and a decrease of NCAM immunoreactivity along with an increase of tPA activity in the CA3 area of the hippocampus. These results suggest that activation of the tPA plasmin system after KA injection into the LCVs results in the degradation of NCAM in the CA3 area.