The relationship between uncoupling of oxidative phosphorylation and neuronal necrosis within the CNS in rats dosed with trihalogenated imidazoles

The trihalogenated imidazoles, trichloroimidazole (TCI), tribromoimidazole (TBI), and triiodoimidazole (TII), are in vitro uncouplers of oxidative phosphorylation with similar activities. Although TCI and TBI are also uncouplers in vitro, some doubt exists for TII, which is much less toxic and produces atypical signs of poisoning. Dibromo- and monobromoimidazole do not uncouple oxidative phosphorylation either in vitro or in vivo. Dosing of TCI and TBI to rats resulted within 24–48 hr in neuronal necrosis within the CNS involving the vestibular nucleus, red nucleus, and outer parietal neocortex and ataxia of the hindlimbs. However, no neuronal necrosis or ataxia was observed after dosing of TII to rats, even when given at doses four times greater than for either TCI or TBI, resulting in much higher brain concentrations. Although TBI was equitoxic to rats, mice, hamsters, and gerbils, CNS damage and ataxia were observed only in the rat, even though comparable brain concentrations of TBI were found in the gerbil. Measurement of the concentration of TBI in the dissected rat brain gave no indication of localized concentrations of compound in the areas associated with neuronal damage. Doses of TBI and the classical uncoupler 3,5-dinitro- o-cresol (DNOC), matched for whole body O 2 consumption, caused comparable changes in rat brain blood flow although DNOC does not cause brain damage. Changes in blood flow were not restricted to those brain areas susceptible to damage. Thus, although we were unable to completely dissociate CNS damage from uncoupling of oxidative phosphorylation produced by TBI and TCI in the rat, it is unlikely that such damage is primarily related to the uncoupling ability of these compounds.