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

The present study assessed whether tumor necrosis factor-α (TNFα) is involved in hemorrhage following large clot embolism-induced ischemia in New Zealand white rabbits by intracisternally administering either TNFα or a goat-anti-rabbit-TNFα antibody following a stroke. The first aim of the study showed that TNFα 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-TNFα antibody. In the tPA-anti-TNFα antibody group, the absolute hemorrhage rate was 38.8% and the hemorrhage volume was 98% of control. In conclusion, following an embolic stroke, TNFα administration increased the incidence and volume of hemorrhage and an anti-TNFα antibody counteracted tPA-induced hemorrhage. The results suggest that TNFα may either be directly or indirectly involved in vascular damage following an embolic stroke. Moreover, TNFα may mediate some of the detrimental effects of tPA on the vascular compartment. Based upon our studies, TNFα receptor antagonists or TNFα processing inhibitors should be further pursued as targets for the treatment of hemorrhagic stroke as adjuvant treatment for stroke patients receiving thrombolytic treatment.