Tumor necrosis factor-alpha is involved in thrombolytic-induced hemorrhage following embolic strokes in rabbits

The present study assessed whether tumor necrosis factor-alpha (TNFalpha) is involved in hemorrhage following large clot embolism-induced ischemia in New Zealand white rabbits by intracisternally administering either TNFalpha or a goat-anti-rabbit-TNFalpha antibody following a stroke. The first aim of the study showed that TNFalpha administration increased stroke-induced hemorrhage incidence to 53.3% from 18.5% (an increase of 188%) in the control group and also increased hemorrhage volume by 87% (p<0.05). The second aim showed that administration of tissue plasminogen activator (tPA) using a standard dose of 3.3 mg/kg increased hemorrhage incidence in rabbits to 76.5% from 18.5% (an increase of 314%) and this effect was reversed by administration of an anti-TNFalpha antibody. In the tPA-anti-TNFalpha antibody group, the absolute hemorrhage rate was 38.8% and the hemorrhage volume was 98% of control. In conclusion, following an embolic stroke, TNFalpha administration increased the incidence and volume of hemorrhage and an anti-TNFalpha antibody counteracted tPA-induced hemorrhage. The results suggest that TNFalpha may either be directly or indirectly involved in vascular damage following an embolic stroke. Moreover, TNFalpha may mediate some of the detrimental effects of tPA on the vascular compartment. Based upon our studies, TNFalpha receptor antagonists or TNFalpha processing inhibitors should be further pursued as targets for the treatment of hemorrhagic stroke as adjuvant treatment for stroke patients receiving thrombolytic treatment.