Combined effects of β-hydroxybutyrate and therapeutic hypothermia in a neonatal hypoxia-ischemia model

Hypoxia-ischemia (HI) is one of the leading causes of brain damage during the development of newborns. It can result in death or cause varying degrees of neurological disability. The only well-established treatment currently available for neonatal HI is therapeutic hypothermia (TH). However, TH is only partially protective, reducing severe disability by approximately 11%. Therefore, new therapeutic approaches are urgently needed. It is known that immature brains utilize higher levels of ketone bodies, such as β-hydroxybutyrate (BHB), that may contribute to resistance to hypoxic-ischemic events. In this study, 11-day-old animals were subjected to the neonatal HI (Rice-Vannucci model) and treated with TH alone or in combination with BHB administration. To assess brain metabolism, glucose uptake was evaluated using MicroPET at 72 hours post-injury and when the animals reached 65 days of age. Behavioral tests, brain volume analysis, hippocampal cell counting and the assessment of hippocampal inflammatory cytokines expression were also performed. Animals treated with BHB exhibited increased glucose uptake at 72 hours post-injury and a reduction in neuronal loss in the hippocampus. The combined use of BHB and TH resulted in enhanced hippocampal neuronal survival, suggesting that BHB may represent a promising future treatment for neonatal HI.