D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease

We show that the infusion of the ketone body D-β-hydroxybutyrate in mice confers partial protection against dopaminergic neurodegeneration and motor deficits induced by MPTP

Kim Tieu


Scholarcy highlights

  • Parkinson disease is the second most common neurodegenerative disease after Alzheimer disease
  • The present study shows that the ketone body DβHB, a crucial alternative source of glucose for brain energy, confers protection against the structural and functional deleterious effects of the parkinsonian toxin MPTP; these include degeneration of substantia nigra pars compacta dopaminergic neurons and striatal dopaminergic fibers, loss of striatal dopamine, and PD-like motor deficit
  • While DβHB levels in the brain were stable in DβHB-infused mice exposed to MPTP, in mice injected with saline they were higher at the beginning and dropped during the experimental period of 7 days
  • The basis for these differences remains to be elucidated, it is possible that the utilization of DβHB in the brain increases rapidly following exposure to mitochondrial poisons such as MPTP and augments progressively in normal brain as part of a metabolic adaptation to sustained high DβHB concentrations
  • Utilization of DβHB in the brain is contingent on its conversion to acetoacetate by β-hydroxybutyrate dehydrogenase, which is scarce in the adult brain, especially in the basal ganglia
  • At 100 μM MPP+ and 100 nM rotenone inhibits more than 90% of the oxygen consumption in glutamate- and malatesupported mitochondrial respiration
  • The activity of β-hydroxybutyrate dehydrogenase correlates with its protein content, and, following MPTP administration, it is upregulated in the ventral midbrain
  • Consistent with the oxygen-consumption data, we found that the stimulation of ATP production by DβHB likely relies on complex II, as inhibitors of this electron transport chain enzyme eliminated the effect

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