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 trig gers the production of tumor necrosis factor alpha (TNF alpha) in the contused hemisphere. Other investigations have shown that this cytokin e plays a role in the inflammatory response following trauma. The pres ent study was designed to determine whether inhibition of TNF alpha pr oduction or activity affects the development of cerebral edema as well as neurological dysfunction and hippocampal cell loss after CHI. To t his end, we used two pharmacological agents, each acting via a differe nt mechanism: pentoxifylline (PTX), which attenuates the production of TNF alpha, and tumor necrosis factor binding protein (TBP), a physiol ogical inhibitor of TNF alpha activity. Both agents significantly less ened peak edema formation at 24 h and facilitated the recovery of moto r function for less than or equal to 14 days postinjury. In addition, TBP attenuated disruption Of the blood-brain barrier and protected hip pocampal cells. PTX significantly lowered the brain TNF alpha level (b y similar to 80%), and TBP completely abolished the activity Of recomb inant 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 .