Tissue Type Plasminogen Activator Facilitates NMDA-Receptor–Mediated Retinal Apoptosis through an Independent Fibrinolytic Cascade

PURPOSE: To investigate the association between apoptosis and the fibrinolytic system in retinal cell damage. METHODS: Tissue type plasminogen activator-deficient (tPA(-/-)), urokinase type plasminogen activator-deficient (uPA(-/-)), plasminogen activator inhibitor-1-deficient (PAI-1(-/-)), alpha2 antiplasmin-deficient (alpha2 AP(-/-)) mice, and their wild-type counterparts were used. Retinal cell damage was induced by intravitreal injection of the excitotoxin N-methyl-d-aspartate (NMDA). The TdT-dUTP terminal nick-end labeling (TUNEL) method was used to examine retinal cell damage. RESULTS: tPA(-/-) mice were resistant to retinal cell damage caused by administration of NMDA, and PAI-1(-/-) mice were more injured than their wild-type. No significant difference was observed between uPA(-/-) or alpha2 AP(-/-) and their wild-type mice. CONCLUSIONS: The results strongly suggest that endogenous tPA, but not uPA acts as a facilitator in NMDA-induced retinal cell damage, and that its mechanism may not be associated with cleavage of plasminogen into plasmin in the fibrinolytic cascade.