Inhibition of tumor necrosis factor alpha (TNF alpha) activity in rat brain is associated with cerebroprotection after closed head injury

We recently demonstrated that closed head injury (CHI) in the rat triggers the production of tumor necrosis factor alpha (TNF alpha) in the contused hemisphere. Other investigations have shown that this cytokine plays a role in the inflammatory response following trauma. The present study was designed to determine whether inhibition of TNF alpha production or activity affects the development of cerebral edema as well as neurological dysfunction and hippocampal cell loss after CHI. To this end, we used two pharmacological agents, each acting via a different mechanism: pentoxifylline (PTX), which attenuates the production of TNF alpha, and tumor necrosis factor binding protein (TBP), a physiological inhibitor of TNF alpha activity. Both agents significantly lessened peak edema formation at 24 h and facilitated the recovery of motor function for less than or equal to 14 days postinjury. In addition, TBP attenuated disruption Of the blood-brain barrier and protected hippocampal cells. PTX significantly lowered the brain TNF alpha level (by similar to 80%), and TBP completely abolished the activity Of recombinant human TNF when they were added at the same time in the in vitro bioassay. We suggest, therefore, that a decrease in TNF alpha level or the inhibition of its activity is accompanied by reduced brain damage.