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

Pietro Ghezzi, Silvio Garattini, Tiziana Mennini, Riccardo Bertini, René Delgado Hernandez, Fabio Benigni, Silvano Sacco, Malgorzata Skorupska, Manuela Mengozzi, Roberto Latini, Mami Kurosaki, Alain Lombet, Arnel Fradin, Jacqueline Bonnet, Yves Rolland, Jean Daniel Brion

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)369-376
Number of pages8
JournalEuropean Journal of Pharmacology
Volume317
Issue number2-3
DOIs
Publication statusPublished - Dec 19 1996

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Keywords

  • Chlorpromnzine
  • Endotoxin
  • TNF (tumor necrosis factor)

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Ghezzi, P., Garattini, S., Mennini, T., Bertini, R., Hernandez, R. D., Benigni, F., Sacco, S., Skorupska, M., Mengozzi, M., Latini, R., Kurosaki, M., Lombet, A., Fradin, A., Bonnet, J., Rolland, Y., & Brion, J. D. (1996). Mechanism of inhibition of tumor necrosis factor production by chlorpromazine and its derivatives in mice. European Journal of Pharmacology, 317(2-3), 369-376. https://doi.org/10.1016/S0014-2999(96)00728-5