Mechanism of inhibition of tumor necrosis factor production by chlorpromazine and its derivatives in mice

• Published in: European journal of pharmacology Vol. 317; no. 2; pp. 369 - 376
• Main Authors: Ghezzi, Pietro, Garattini, Silvio, Mennini, Tiziana, Bertini, Riccardo, Hernandez, René Delgado, Benigni, Fabio, Sacco, Silvano, Skorupska, Malgorzata, Mengozzi, Manuela, Latini, Roberto, Kurosaki, Mami, Lombet, Alain, Fradin, Arnel, Bonnet, Jacqueline, Rolland, Yves, Brion, Jean-Daniel
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 19.12.1996; Elsevier
• Subjects: Animals; Antioxidants - pharmacology; Biological and medical sciences; Blood Pressure - drug effects; Chlorpromazine; Chlorpromazine - analogs & derivatives; Chlorpromazine - pharmacology; Depression, Chemical; Endotoxin; Enzyme Inhibitors - pharmacology; In Vitro Techniques; Lipopolysaccharides - pharmacology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Motor Activity - drug effects; Neuropharmacology; Neuroprotective agent; Nitric Oxide Synthase - antagonists & inhibitors; Pharmacology. Drug treatments; Phospholipases A - antagonists & inhibitors; Phospholipases A2; Rats; Rats, Wistar; Receptors, Neurotransmitter - drug effects; Receptors, Neurotransmitter - metabolism; Swine; TNF (tumor necrosis factor); Tumor Necrosis Factor-alpha - biosynthesis; Chlorpromazine; Endotoxin; TNF (tumor necrosis factor); Neuroleptic; Psychotropic; Toxicity; Cytokine; Rodentia; Central nervous system; Lipids; Neuroprotective agent; Phenothiazine derivatives; Antioxidant; Biological activity; Vertebrata; Mammalia; Synthesis; Mouse; Tumor necrosis factor; Animal; Nitric oxide; Antipsychotic; Inhibition; Mechanism of action; Peroxidation
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(96)00728-5

In previous work, we reported that chlorpromazine inhibits tumor necrosis factor (TNF) production in endotoxin lipopolysaccharide-treated mice, and protects against lipopolysaccharide toxicity. Chlorpromazine is used as an antipsychotic and has several effects on the central nervous system. It acts on different neurotransmitter receptors and has other biochemical activities some of which, like inhibition of phospholipase A 2, might be responsible for the inhibitory effect on TNF production. To investigate the role of these actions in the inhibition of TNF production by chlorpromazine, we have synthesized some chlorpromazine derivatives that do not have central activities. Some of these analogs have lost their affinity for various receptors and their phospholipase A 2 inhibitory activity, but still inhibit TNF production. No correlation was found between TNF inhibition and the ability to inhibit nitric oxide (NO) synthase, whereas a good correlation was evident between TNF inhibition and antioxidant activity.