Brain mitochondrial free radical production induced by haloperidol treatment.

LORES ARNAIZ, S.; CORONEL, M.F.; BOVERIS, A.

Sao Paulo

Congreso; IX Biennial Meeting International Society for Free Radical Research; 1998

Society for Free Radical Research

Inhibition of mitochondrial respiration and free radical induction have been suggested to be involved in haloperidol neurotoxicity. In this study, mice were injected i.p. with haloperidol, according to two different treatments: a) a single injection (1 mg/kg), sacrificed 1 hour after the injection (single-dose model), and b) two injections (1 mg/kg each), sacrificed 24 hours after the first dose (double-dose model). Determinations of oxygen consumption and hydrogen peroxide (H2O2) production rate were carried out in isolated brain mitochondria. Nitric oxide (?NO) and superoxide (O2-) production rates were measured in submitochondrial particles (SMP). Single-dose haloperidol treatment produced a 33% inhibition in malate-glutamate-dependent respiration rate, one hour after drug injection, while no significant changes were found after 24 hours (double-dose treatment). Mitochondrial H2O2 production rate was increased by 54% in the presence of succinate, after haloperidol single-dose treament. ?NO production was inhibited by 39% and 54% in SMP from haloperidol-treated mice (single- and double-dose treatments respectively) (control value: 1.6  0.2 nmol/min.mg protein). ?NO steady-state concentration was estimated about 3.2 nM and was decreased by 50% by haloperidol treatment. Single-dose treatment generated a 248% increase in SMP O2- production rate when measured in the presence of NADH plus rotenone, and a 105% increase in its production rate when measured in the presence of succinate. Our results suggest that haloperidol neurotoxicity would be mediated by inhibition of mitochondrial electron transfer and enhancement of O2- and H2O2 production. This inhibition does not seem to be caused by increased ?NO or ONOO- formation.