BETA-HYDROXYBUTYRATE MONOESTER TREATMENT PREVENTS CELL DEATH AND ATTENUATES THE UNFOLDED PROTEIN RESPONSE IN MICE FOLLOWING EXCITOTOXIC HIPPOCAMPAL INJURY

Attenuation of the unfolded protein response (UPR), a cellular stress pathway that restores proteostasis or induces cell death when endoplasmic reticulum stress remains unresolved, is closely associated with cell survival during acute brain injury. Beta-hydroxybutyrate (BHB), a ketone body naturally produced during fasting or ketogenic diets, has been shown to reduce UPR activation and lesion volume in ischemic conditions. In addition, orogastric administration of a BHB monoester dietary supplement (Delta-G) decreases lesion volume caused by traumatic brain injury in rodents. However, the molecular mechanisms underlying UPR modulation by BHB during brain injury remain poorly understood. This study aimed to characterize UPR activation following an excitotoxic lesion in the hippocampus and to evaluate whether Delta-G administration attenuates UPR signaling and reduces lesion volume. Male mice received an intrahippocampal microinjection of N-methyl-D-aspartate (NMDA) into the dorsal hippocampus and were subsequently treated for five consecutive days with daily orogastric administration of Delta-G. Body weight, food and water intake, blood ketone and glucose levels, activation of UPR effectors (GRP78, pIRE1α, pPERK, and peIF2α), and lesion volume were assessed at 1, 3, and 5 days post-injury. UPR effectors were differentially activated over time following excitotoxic hippocampal injury. Delta-G reduced body weight and food intake and increased ketone body levels. Mice treated with Delta-G after NMDA injection exhibited altered UPR dynamics and reduced lesion volume. These findings suggest that short-term orogastric Delta-G administration confers neuroprotection by modulating UPR-related pathways, supporting its potential as a non-invasive therapeutic strategy for acute brain injuries. Supported by grant IN215825 PAPIIT-UNAM.