Chlorpromazine (CPZ) is an effective
cyanide antidote, with its greatest efficacy displayed when combined with the antidotes,
sodium nitrite and
sodium thiosulfate. Since the central nervous system is a primary target organ in
cyanide toxicity, the objective of the present study was to determine the mechanisms by which CPZ prevents
cyanide-induced damage in neural systems. KCN (10 mM) increased cytosolic free
calcium in rat
pheochromocytoma (PC12) cells as indicated by the
fluorescent dye quin 2. This was blocked by addition of CPZ (0.1 mM) to the cells 15 min prior to addition of KCN. Incubation of cells with KCN (0.1 mM) increased the levels of
lipid conjugated dienes and this was blocked by addition of CPZ (1 microM). Peroxidation of brain
lipids in mice administered KCN (7-15 mg/kg, sc) was also attenuated by pretreatment with CPZ. Furthermore, production of lipid peroxidation in fresh mouse brain slices, following incubation with 0.1 mM KCN, was blocked by simultaneous addition of CPZ. These observations indicate CPZ prevents
cyanide-induced
calcium influx and decreases peroxidation of
membrane lipids. Thus the antidotal activity of CPZ in
cyanide toxicity appears to be related to maintenance of cellular
calcium homeostasis and membrane integrity.