Chlorpromazine down-regulates tumor necrosis factor-α and attenuates experimental multiple organ dysfunction syndrome in mice

Objectives: Chlorpromazine is a known modulator of tumor necrosis factor (TNF)-alpha production, TNF-alpha is thought to be a key mediator in the development of the multiple organ dysfunction syndrome (MODS), We investigated the effect of chlorpromazine on the development of zymosan-induced MODS in mice and on plasma TNF-alpha concentrations and production capacity of TNF-alpha by peritoneal cells. Design: prospective, controlled laboratory study on zymosan induced generalized inflammation in mice. Setting: Animal research laboratory. Subjects: C57BL/6 mice received daily doses (4 mg/kg body weight) of chlorpromazine, beginning 2 days before or 5 days after zymosan administration. In additional groups, the daily chlorpromazine dose of 4 mg/kg started 5 days after zymosan was increased 2 days later to 8 or 16 mg/kg/day. Measurements and Main Results: The animals were monitored for survival, condition, body weight, and body temperature. Twelve days after zymosan was administered, all surviving animals were killed to obtain plasma, organs, and peritoneal cells. Plasma concentrations of TNF-alpha and lipopolysaccharide-stimulated production of TNF-alpha by peritoneal cells were measured. Organ weights were recorded as an indicator for organ damage. Although survival was not improved when the animals were treated with chlorpromazine, the chlorpromazine-treated survivors showed improved body weight and temperature when compared with the animals receiving zymosan only. Also, the organ weights and lung damage improved significantly in the treated group, Chlorpromazine was most effective when started before zymosan administration, When administered afterward, clinical improvement declined with the dose. In all cases, circulating TNF-alpha and production of TNF-alpha by peritoneal macrophages were lowered toward control values. Conclusion: Chlorpromazine mitigates the development of zymosan-induced MODS, possibly by reducing macrophage TNF-alpha production.