Exogenous β-Hydroxybutyrate Treatment and Neuroprotection in a Suckling Rat Model of Hypoxic-Ischemic Encephalopathy.

β-Hydroxybutyrate (BHB) is a representative ketone body that may play a role in the mitigation of neonatal hypoxic-ischemic encephalopathy by altering energy metabolism. This study aimed to investigate the neuroprotective efficacy of exogenous BHB administration in a suckling rat model after hypoxia-ischemia (HI). Thirteen-day-old (P13) rat pups were subjected to 120 min of hypoxia according to the Rice-Vannucci model. BHB (5.0 mmol/kg, HI-BHB) or vehicle (0.9% saline, HI-Veh) was administered 0, 2, 4, and 6 h after HI induction. Pathologic injury scores and the number of TUNEL-positive cells were evaluated on P15. Residual hemispheric volume was measured with T2-weighted MRI (on P27) and functional tests, such as the negative geotaxis test, rope suspension test, rotarod test, novel object recognition test, and cylinder test, were performed. Systemic ketosis (approx. 2.0-3.0 mM/L) was well tolerated by the rat pups with no difference in the mortality rate between both groups. Compared with the HI-Veh group, the HI-BHB group demonstrated significantly lower pathological scores as well as fewer TUNEL-positive cells. The intact residual hemispheric and hippocampal volumes were greater in the HI-BHB group than the HI-Veh group. However, the results of functional tests did not differ between both groups. Postischemic BHB administration reduced brain injury in suckling rats after HI. The safe clinical application of our animal model to human infants with HI requires further investigation.