TY - JOUR
T1 - Mechanism of inhibition of tumor necrosis factor production by chlorpromazine and its derivatives in mice
AU - Ghezzi, Pietro
AU - Garattini, Silvio
AU - Mennini, Tiziana
AU - Bertini, Riccardo
AU - Hernandez, René Delgado
AU - Benigni, Fabio
AU - Sacco, Silvano
AU - Skorupska, Malgorzata
AU - Mengozzi, Manuela
AU - Latini, Roberto
AU - Kurosaki, Mami
AU - Lombet, Alain
AU - Fradin, Arnel
AU - Bonnet, Jacqueline
AU - Rolland, Yves
AU - Brion, Jean Daniel
PY - 1996/12/19
Y1 - 1996/12/19
N2 - 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.
AB - 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.
KW - Chlorpromnzine
KW - Endotoxin
KW - TNF (tumor necrosis factor)
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U2 - 10.1016/S0014-2999(96)00728-5
DO - 10.1016/S0014-2999(96)00728-5
M3 - Article
C2 - 8997623
AN - SCOPUS:0030593904
VL - 317
SP - 369
EP - 376
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 2-3
ER -