Glucose is the main energy substrate in brain but in certain circumstances such as prolonged fasting and the suckling period alternative substrates can be used such as the ketone bodies (KB), beta-hydroxybutyrate (BHB), and acetoacetate. It has been shown that KB prevent neuronal death induced during energy limiting conditions and excitotoxicity. The protective effect of KB has been mainly attributed to the improvement of mitochondrial function. In the present study, we have investigated the protective effect of D-BHB against neuronal death induced by severe noncoma hypoglycemia in the rat in vivo and by glucose deprivation (GD) in cortical cultures. Results show that systemic administration of D-BHB reduces reactive oxygen species (ROS) production in distinct cortical areas and subregions of the hippocampus and efficiently prevents neuronal death in the cortex of hypoglycemic animals. In vitro results show that D-BHB stimulates ATP production and reduces ROS levels, while the nonphysiologic isomer of BHB, L-BHB, has no effect on energy production but reduces ROS levels. Data suggest that protection by BHB, not only results from its metabolic action but is also related to its capability to reduce ROS, rendering this KB as a suitable candidate for the treatment of ischemic and traumatic injury.
INTRODUCTIONGlucose is the main energy source in brain. However, under certain conditions other energy substrates such as the ketone bodies (KB), acetoacetate (AcAc), and β-hydroxybutyrate (BHB) can be used by brain, including the suckling period, 1,2 prolonged fasting, 3 and the ketogenic diet; 4 all these situations are associated with increased KB levels in blood. Several studies have shown that KB can protect the brain against damage associated with diverse neurotoxic insults such as hypoxia, 5 ischemia, 6-8 hypoglycemia, 9,10 and excitotoxicity. 11,12 In addition, the ketogenic diet has been used for a long time for the treatment of refractory epilepsy. 4,13,14 The protective effect of KB has been mostly attributed to their conversion to AcetylCoA improving mitochondrial metabolism and preserving energy levels. [15][16][17] However, studies suggest that besides providing energy to neurons, KB reduce the production of reactive oxygen species (ROS) contributing to their protective effect. It has been observed in vitro that AcAc reduces ROS levels induced by glutamate exposure and glycolysis inhibition in cultured neurons, 12,16 and previous in vivo studies have shown that BHB decreases hypoglycemia and glutamate-mediated lipoperoxidation in the rat brain. 10,18 The mechanism underlying the reduction of ROS by BHB has not been elucidated but we have previously reported that KB display a scavenging action of ROS, in particular of the hydoxyl radical ( • OH). 10 The physiologic and the
