MECHANISM OF INHIBITION OF TUMOR-NECROSIS-FACTOR PRODUCTION BY CHLORPROMAZINE AND ITS DERIVATIVES IN MICE

In previous work, we reported that chlorpromazine inhibits tumor necro sis factor (TNF) production in endotoxin lipopolysaccharide-treated mi ce, and protects against lipopolysaccharide toxicity. Chlorpromazine i s used as an antipsychotic and has several effects on the central nerv ous system. It acts on different neurotransmitter receptors and has ot her biochemical activities some of which, like inhibition of phospholi pase A(2), might be responsible for the inhibitory effect on TNF produ ction. To investigate the role of these actions in the inhibition of T NF production by chlorpromazine, we have synthesized some chlorpromazi ne derivatives that do not have central activities. Some of these anal ogs have lost their affinity for various receptors and their phospholi pase A(2) inhibitory activity, but still inhibit TNF production. No co rrelation was found between TNF inhibition and the ability to inhibit nitric oxide (NO) synthase, whereas a good correlation was evident bet ween TNF inhibition and antioxidant activity.