Ketogenic diet protects myelin and axons in diffuse axonal injury

Abstract

ABSTRACT Background Ketogenic diet (KD) has been identified as a potential therapy to enhance recovery after traumatic brain injury (TBI). Diffuse axonal injury (DAI) is a common type of traumatic brain injury that is characterized by delayed axonal disconnection. Previous studies showed that demyelination resulting from oligodendrocyte damage contributes to axonal degeneration in DAI. Aim The present study tests a hypothesis that ketone bodies from the ketogenic diet confers protection for myelin and attenuates degeneration of demyelinated axon in DAI. Methods A modified Marmarou’s model of DAI was induced in adult rats. The DAI rats were fed with KD and analyzed with western blot, transmission electron microscope, ELISA test and immunohistochemistry. Meanwhile, a co-culture of primary oligodendrocytes and neurons was treated with ketone body β-hydroxybutryate (βHB) to test for its effects on the myelin-axon unit. Results Here we report that rats fed with KD showed an increased fatty acid metabolism and ketonemia. This dietary intervention significantly reduced demyelination and attenuated axonal damage in rats following DAI, likely through inhibition of DAI-induced excessive mitochondrial fission and promoting mitochondrial fusion. In an in vitro model of myelination, the ketone body βHB increased myelination significantly and reduced axonal degeneration induced by glucose deprivation (GD). βHB robustly increased cell viability, inhibited GD-induced collapse of mitochondrial membrane potential and attenuated death of oligodendrocytes. Conclusion Ketone bodies protect myelin-forming oligodendrocytes and reduce axonal damage. Ketogenic diet maybe a promising therapy for DAI.