Synergism between tumor necrosis factor-α and H₂O ₂ enhances cell damage in rat PC12 cells

Tumor necrosis factor-α (TNFα) is harmful in the early phase and beneficial in the long-term phase after brain injury. Reactive oxygen species (ROS) are among the most toxic mediators activated by injury. We speculate that part of the TNFα toxicity is mediated by its synergism with ROS. Thus, toxicity of TNFα and ROS, alone or together, were studied in PC12 cells. PC12 cells were exposed for 18 h to TNFα (0-100 ng/ml), to H₂O₂ (1-300 μM) or to both, each at sub-toxic concentrations. Lactic dehydrogenase release, prostaglandin E₂ accumulation and morphology indicated cell death and stress response. TNFα toxicity was seen at >50 ng/ml, and that of H₂O ₂ at >150 μM, however, when together, sub-lethal levels (25 ng/ml TNFα and 30 μM H₂O₂) induced toxicity. Dexanabinol, an N-methyl-D-aspartate antagonist with antioxidant and anti-TNFα properties, completely rescued the cells. These findings corroborate our hypothesis on the cooperative toxicity exerted by TNFα and ROS after brain injury.