Enhancement of L-3-hydroxybutyryl-CoA dehydrogenase activity and circulating ketone body levels by pantethine. Relevance to dopaminergic injury

BMC Neuroscience

Research Article

André Nieoullon¹  Mhamad Abou-Hamdan²  Michel Khrestchatisky²  Emilie Cornille²  Bouchra Gharib²  Max de Reggi² 

[1] Institut de Biologie du Développement, UMR CNRS 6216, Université de la Méditerranée, 13009, Marseille, France;Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, UMR CNRS 6184, Université de la Méditerranée, 13015, Marseille, France;

关键词: Dehydrogenase Activity;    Ketone Body;    Ketogenic Diet;    Cysteamine;    Brain Mitochondrion;   

DOI  :  10.1186/1471-2202-11-51

 received in 2009-10-22, accepted in 2010-04-23,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsWe 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.ConclusionsThese 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.

【 授权许可】

Unknown   
© Cornille et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.