title: Mechanism of inhibition of tumor necrosis factor production by chlorpromazine and its derivatives in mice.
abstract: 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 A2, 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 A2 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.
authors.affiliation: Laboratory of Neuroimmunology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Ghezzi
authors.forename: S
authors.initials: S
authors.lastname: Garattini
authors.forename: T
authors.initials: T
authors.lastname: Mennini
authors.forename: R
authors.initials: R
authors.lastname: Bertini
authors.forename: R
authors.initials: R
authors.lastname: Delgado Hernandez
authors.forename: F
authors.initials: F
authors.lastname: Benigni
authors.forename: S
authors.initials: S
authors.lastname: Sacco
authors.forename: M
authors.initials: M
authors.lastname: Skorupska
authors.forename: M
authors.initials: M
authors.lastname: Mengozzi
authors.forename: R
authors.initials: R
authors.lastname: Latini
authors.forename: M
authors.initials: M
authors.lastname: Kurosaki
authors.forename: A
authors.initials: A
authors.lastname: Lombet
authors.forename: A
authors.initials: A
authors.lastname: Fradin
authors.forename: J
authors.initials: J
authors.lastname: Bonnet
authors.forename: Y
authors.initials: Y
authors.lastname: Rolland
authors.forename: J D
authors.initials: JD
authors.lastname: Brion
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002746:Chlorpromazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003864:Depression, Chemical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D051381:Rats; D017208:Rats, Wistar; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D017981:Receptors, Neurotransmitter; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D010741:Phospholipases A; D054467:Phospholipases A2; D002746:Chlorpromazine