title: Enhancement of L-3-hydroxybutyryl-CoA dehydrogenase activity and circulating ketone body levels by pantethine. Relevance to dopaminergic injury.
abstract: BACKGROUND
  The administration of the ketone bodies hydroxybutyrate and acetoacetate is known to exert a protective effect against metabolic disorders associated with cerebral pathologies. This suggests that the enhancement of their endogenous production might be a rational therapeutic approach. Ketone bodies are generated by fatty acid beta-oxidation, a process involving a mitochondrial oxido-reductase superfamily, with fatty acid-CoA thioesters as substrates. In this report, emphasis is on the penultimate step of the process, i.e. L-3-hydroxybutyryl-CoA dehydrogenase activity. We determined changes in enzyme activity and in circulating ketone body levels in the MPTP mouse model of Parkinson's disease. Since the active moiety of CoA is pantetheine, mice were treated with pantethine, its naturally-occurring form. Pantethine has the advantage of being known as an anti-inflammatory and hypolipidemic agent with very few side effects.
  
  
  RESULTS
  We found that dehydrogenase activity and circulating ketone body levels were drastically reduced by the neurotoxin MPTP, whereas treatment with pantethine overcame these adverse effects. Pantethine prevented dopaminergic neuron loss and motility disorders. In vivo and in vitro experiments showed that the protection was associated with enhancement of glutathione (GSH) production as well as restoration of respiratory chain complex I activity and mitochondrial ATP levels. Remarkably, pantethine treatment boosted the circulating ketone body levels in MPTP-intoxicated mice, but not in normal animals.
  
  
  CONCLUSIONS
  These finding demonstrate the feasibility of the enhancement of endogenous ketone body production and provide a promising therapeutic approach to Parkinson's disease as well as, conceivably, to other neurodegenerative disorders.
authors.affiliation: Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, UMR CNRS 6184, Université de la Méditerranée, 13015 Marseille, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Cornille
authors.forename: Mhamad
authors.initials: M
authors.lastname: Abou-Hamdan
authors.forename: Michel
authors.initials: M
authors.lastname: Khrestchatisky
authors.forename: André
authors.initials: A
authors.lastname: Nieoullon
authors.forename: Max
authors.initials: M
authors.lastname: de Reggi
authors.forename: Bouchra
authors.initials: B
authors.lastname: Gharib
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001928:Brain Diseases, Metabolic / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006884:Hydroxybutyrate Dehydrogenase / Q000187:drug effects* / Q000378:metabolism; D007657:Ketone Bodies / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010204:Pantetheine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D000214:Acyl Coenzyme A; D007657:Ketone Bodies; D018696:Neuroprotective Agents; C030372:3-hydroxybutyryl-coenzyme A; D010204:Pantetheine; C005425:pantethine; D000255:Adenosine Triphosphate; D006884:Hydroxybutyrate Dehydrogenase; D042967:Electron Transport Complex I; D005978:Glutathione; D004298:Dopamine