Neurosteroid levels are increased in vivo after LPS treatment and negatively regulate LPS-induced TNF production

Neuroactive steroids such as dehydroepiandrosterone sulfate and pregnenolon e inhibit lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) prod uction. Corticosteroids not only inhibit TNF production but their levels ar e increased in vivo after endotoxin injection, thus representing a feedback system that limits TNF production. We wondered whether the same could be t rue for neuroactive steroids. Thus, the possibility that neuroactive steroi ds might be increased concomitantly to TNF induction in vivo in mice treate d with LPS was investigated. Increased plasma and hippocampal levels of all opregnanolone (but not of dehydroepiandrosterone or pregnenolone) were foun d 90 min after LPS injection. Allopregnanolone and progesterone (IC50 10(-7) and 10(-9) M, respectively) also inhibited TNF production by mouse peritoneal macrophages in vitro at c oncentrations in the range of those detected in vivo. These findings sugges t that neuroactive steroids may act as endogenous inhibitors of cerebral an d systemic TNF production.