FROM undetectable basal levels, TNFα is produced in the hypothalamus of rats challenged with a systemic low profile endotoxin (LPS) at least 30 min before its release may be detected in the plasma. The cytotoxic activity of this hypothalamic TNFα correlates with its immunore-activity. Injection of BB-1101, a matrix metalloprotease inhibitor, immediately after the LPS totally inhibits the plasma LPS-induced TNFα release without affecting the hypothalamic TNFα response. Likewise, L-NAME pretreatment, a nitric oxide inhibitor which reportedly crosses the blood-brain barrier, blunts the plasma TNFα response by almost 66%, but leaves the hypothalamic TNFα response unchanged. The present study thus describes the early occurrence of hypothalamic TNFα in response to systemic LPS injection, which is not subjected to the same regulations as plasma TNFα.