Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions

Ketone bodies play a key role in mammalian energy metabolism during the suckling period. Normally ketone bodies' blood concentration during adulthood is very low, although it can rise during starvation, an exogenous infusion or a ketogenic diet. Whenever ketone bodies' levels increase, their oxidation in the brain rises. For this reason they have been used as protective molecules against refractory epilepsy and in experimental models of ischemia and excitotoxicity. The mechanisms underlying the protective effect of these compounds are not completely understood. Here, we studied a possible antioxidant capacity of ketone bodies and whether it contributes to the protection against oxidative damage induced during hypoglycemia. We report for the first time the scavenging capacity of the ketone bodies, acetoacetate (AcAc) and both the physiological and non-physiological isomers of β-hydroxybutyrate (d- and l-BHB, respectively), for diverse reactive oxygen species (ROS). Hydroxyl radicals (OH) were effectively scavenged by d- and l-BHB. In addition, the three ketone bodies were able to reduce cell death and ROS production induced by the glycolysis inhibitor, iodoacetate (IOA), while only d-BHB and AcAc prevented neuronal ATP decline. Finally, in an in vivo model of insulin-induced hypoglycemia, the administration of d- or l-BHB, but not of AcAc, was able to prevent the hypoglycemia-induced increase in lipid peroxidation in the rat hippocampus. Our data suggest that the antioxidant capacity contributes to protection of ketone bodies against oxidative damage in in vitro and in vivo models associated with free radical production and energy impairment.