Neuroprotective effects of β-hydroxybutyrate in a post-traumatic stress disorder model: Behavioral, endocrine, and amygdala-hippocampal apoptotic modulation in male and female rats.

Post-traumatic stress disorder (PTSD) often involves disrupted neuroendocrine, inflammatory, and cell death pathways. In this study, we investigated the neuroprotective effects of β-hydroxybutyrate (BHB) on a PTSD model in male and female Wistar rats. Rats were exposed to a PTSD-like model, and twenty-four hours later, they received BHB (250 mg/kg) or glucose (5 %) twice daily, for seven days. Twelve hours after the last injection, the rats were challenged on behavioral tests for locomotor activity, anxiety-like phenotype, and contextual fear-related behaviors. Twenty-four hours after the last behavioral test, samples of serum, amygdala, and hippocampus were collected. Corticosterone, anxiety index, and freezing behavior were increased, and the expression of GRα/β, FKBP51, BAX/Bcl-2, and TNFα in the amygdala and hippocampus were different in the PTSD rats. BHB prevented behavioral deficits, normalized corticosterone and GR, and apoptosis signaling in both sexes, but glucose did not rescue these alterations. In females, inflammatory mediators (TNFα, IBA-1) were enhanced and partially suppressed by BHB. Correlations between anxiety-like phenotype and fear behaviors, and between measures of behaviors and levels of molecular and corticosterone changes, indicate a unified stress response. Our findings suggest that BHB shows promise as a neuroprotective treatment for PTSD in both male and female rats.