Tissue type plasminogen activator amplifies hemoglobin-induced neurotoxicity in rat neuronal cultures

Tissue type plasminogen activator (tPA) is clinically used as a form of thrombolytic therapy for acute ischemic stroke. However, recent data suggest that there may be negative effects associated with tPA. Experimental studies show that tPA amplifies excitotoxic neuronal damage and clinical trials show that some stroke patients suffer from hemorrhage after tPA therapy. Since hemoglobin is the major component of blood, we tested the hypothesis that tPA can amplify hemoglobin-induced neurotoxicity. PC12 cells and primary cortical rat neurons were exposed to either hemoglobin alone or hemoglobin plus tPA. Hemoglobin induced dose-dependent cytotoxicity. The addition of tPA significantly increased hemoglobin-induced cell death. These results raise the important possibility that tPA may worsen outcomes after hemorrhage.