Nitric oxide, superoxide, and hydrogen peroxide production in brain mitochondria after haloperidol treatment.
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 h after the injection (single-dose model); and (b) two injections (1 mg/kg each), sacrificed 24 h 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, while no significant changes were found after 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 at about 16.5 nM and was decreased by 40% by haloperidol treatment. Increases of 105 and 54% were found in succinate-supported O2- and H2O2 production rates, respectively, after haloperidol single-dose treatment. Haloperidol treatment generated a 248% increase in SMP O2- production rate when measured in the presence of NADH plus rotenone. Our results suggest that haloperidol neurotoxicity would be mediated by a decreased mitochondrial NO production, a decreased intramitochondrial NO steady-state concentration, and by an inhibition of mitochondrial electron transfer with enhancement of O2- and H2O2 production. This inhibition does not seem to be caused by increased NO or ONOO- formation.
Arnaiz
S L
SL
School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina. slarnaiz@ffyb.uba.ar
Coronel
M F
MF
Boveris
A
A
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004334:Drug Administration Schedule; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007700:Kinetics; D008293:Malates / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D013367:Submitochondrial Particles / Q000187:drug effects / Q000378:metabolism; D013379:Substrate Specificity; D013386:Succinates / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
D008293:Malates; D013386:Succinates; D013481:Superoxides; D009569:Nitric Oxide; D018698:Glutamic Acid; D006861:Hydrogen Peroxide; D006220:Haloperidol