title: D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease.
abstract: 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.
authors.affiliation: Department of Neurology, Columbia University, New York, New York, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Tieu
authors.forename: Celine
authors.initials: C
authors.lastname: Perier
authors.forename: Casper
authors.initials: C
authors.lastname: Caspersen
authors.forename: Peter
authors.initials: P
authors.lastname: Teismann
authors.forename: Du-Chu
authors.initials: DC
authors.lastname: Wu
authors.forename: Shi-Du
authors.initials: SD
authors.lastname: Yan
authors.forename: Ali
authors.initials: A
authors.lastname: Naini
authors.forename: Miquel
authors.initials: M
authors.lastname: Vila
authors.forename: Vernice
authors.initials: V
authors.lastname: Jackson-Lewis
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
mesh_terms: 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
chemical_list: 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