D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease.
Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of the nigrostriatal dopaminergic neurons accompanied by a deficit in mitochondrial respiration. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes dopaminergic neurodegeneration and a mitochondrial deficit reminiscent of PD. Here we show that the infusion of the ketone body d-beta-hydroxybutyrate (DbetaHB) in mice confers partial protection against dopaminergic neurodegeneration and motor deficits induced by MPTP. These effects appear to be mediated by a complex II-dependent mechanism that leads to improved mitochondrial respiration and ATP production. Because of the safety record of ketone bodies in the treatment of epilepsy and their ability to penetrate the blood-brain barrier, DbetaHB may be a novel neuroprotective therapy for PD.
Tieu
Kim
K
Department of Neurology, Columbia University, New York, New York, USA.
Perier
Celine
C
Caspersen
Casper
C
Teismann
Peter
P
Wu
Du-Chu
DC
Yan
Shi-Du
SD
Naini
Ali
A
Vila
Miquel
M
Jackson-Lewis
Vernice
V
Ramasamy
Ravichandran
R
Przedborski
Serge
S
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D020155:3-Hydroxybutyric Acid / Q000378:metabolism* / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology; D042967:Electron Transport Complex I; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006884:Hydroxybutyrate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009043:Motor Activity / Q000502:physiology; D009243:NAD / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D016877:Oxidants / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015259:Dopamine Agents; D018696:Neuroprotective Agents; D016877:Oxidants; D009243:NAD; D000255:Adenosine Triphosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006861:Hydrogen Peroxide; D006884:Hydroxybutyrate Dehydrogenase; D014446:Tyrosine 3-Monooxygenase; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; D010100:Oxygen; D020155:3-Hydroxybutyric Acid; D004298:Dopamine