Brain mitochondrial free radical production induced by haloperidol treatment

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

San Pablo, Brasil

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

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 were carried out in isolated brain mitochondria. Nitric oxide (.NO) and superoxide (O2-) production rates were measured in submitochondrial particles (SMP), and the steady-state concentrations of these species were calculated. 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). .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 O2- production rate (in the presence of NADH and rotenone) and a 3-fold increase in its steady-state concentration. Our results suggest that haloperidol neurotoxicity would be mediated by inhibition of mitochondrial electron transfer and enhancement of O2- production at the NADH dehydrogenase site. This inhibition does not seem to be caused by increased .NO or ONOO- formation.