β-hydroxybutyrate alleviates motor impairment and neurological damage in hypoxic-ischemic encephalopathy mice

Hypoxic-ischemic encephalopathy (HIE) is a major reason for neonatal mortality and long-term neurological deficits, with limited efficacy from current standard treatments like therapeutic hypothermia. β-hydroxybutyrate (BHB) is an abundant ketone body synthesized in the liver, possesses energy supply, anti-inflammatory, antioxidant, and anti-apoptotic activities. This study aims to investigate the effect of exogenous BHB on motor impairments and brain damage in HIE mice. Ten-day-old mouse pups underwent left common carotid artery ligation followed by hypoxia to induce HIE. Control underwent Sham surgery. BHB (300 mg/kg, i.p.) was administered daily for 39 consecutive days. Cylinder and rotarod tests were used to assess long-term functional outcomes, while Nissl and TUNEL staining assessed brain atrophy and apoptosis. Immunofluorescence was used to evaluate neuronal integrity, microglial activation and synaptic density. BHB serum and inflammatory markers in brain were measured using ELISA. Consecutive BHB treatment significantly improved motor function and reduced brain atrophy in HIE mice. These improvements were correlated with a recovery in the number of neurons and synapses in the motor cortex and striatum, alongside a reduction in apoptotic cell death. Furthermore, BHB reduced microglial activation and neuroinflammation. Notably, motor improvement persisted for eight weeks after the cessation of BHB treatment, suggesting long-lasting effects in diminishing lesion impact independent of continuous intervention. Consecutive BHB treatment improves motor function, maintains neuronal architecture, and reduces microglial activation and neuroinflammation in HIE mice, demonstrating sustained benefits in reducing lesion impact. These findings highlight the potential of BHB as a viable therapeutic intervention for HIE.