Mol Neurobiol. 2026 Mar 8;63(1):490. doi: 10.1007/s12035-026-05759-2.
ABSTRACT
The ketogenic diet has attracted increasing interest for its potential neuroprotective effects, mediated by β-hydroxybutyrate (BHB), a ketone body influencing energy metabolism and inflammation. This study examined whether BHB supplementation modulates cellular responses to injury in an in vitro scratch model of traumatic brain injury (TBI). Primary cortical and hippocampal neuron-glia cultures derived from neonatal rats were maintained for 21 days in vitro (DIV). Cultures were supplemented with 5 mM BHB from DIV14 to DIV21. At DIV21, mechanical scratch injury was applied, and cellular responses were assessed 6 h and 24 h post-injury using live-cell migration imaging, Western blotting (GFAP, NeuN), cytokine profiling, immunocytochemistry, and electron microscopy. BHB supplementation was associated with increased astrocyte density in injured cortical and hippocampal cultures and with shifts in astrocyte morphology toward bipolar and intermediate phenotypes, suggesting modulation of astrocyte reactivity. In BHB-supplemented cortical cultures, neuronal density within the injury area was higher compared with non-supplemented controls. BHB reduced levels of the pro-inflammatory cytokine IL-1β and modulated the expression profiles of GM-CSF, IFNγ, and Neuropilin-1, in a region- and time-dependent manner. GFAP expression in hippocampal cultures displayed a biphasic response, indicating dynamic astrocyte regulation following injury. Ultrastructural analysis revealed injury-induced cellular alterations, while BHB-supplemented cultures exhibited features consistent with improved cellular integrity. Collectively, these findings suggest that BHB modulates astrocyte-associated inflammatory responses and supports cellular adaptation following mechanical injury in neuron-glia cultures. While limited to an in vitro setting, this study provides insight into potential mechanisms by which BHB may influence neuroinflammatory processes after TBI.
PMID:41795770 | DOI:10.1007/s12035-026-05759-2
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