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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p

L' hypométabolisme énergétique, une cible pour le traitement des maladies neurodégénératives (Etude de faisabilité)

Toutes les maladies neurodégénératives s accompagnent, à des degrés divers, de dysfonctions métaboliques, avec altération de la glycolyse, source énergétique préférentielle des neurones. Cependant, dans ce cas, le cerveau a la faculté de faire appel à une source énergétique alternative, en mobilisant les réserves lipidiques. Ce processus, dit -oxydation des acides gras, fait intervenir une grande famille d oxydoréductases, dont les substrats sont des acides gras lié au Coenzyme A (CoA) sous forme de thioesters. Ces enzymes présentent de très nombreuses isoformes, répondant à la grande variabilité structurale des acides gras. Cela conduit à la production des corps cétoniques , -hydroxybutyrate et acétoacétate. L administration de ces corps cétoniques a un effet protecteur dans de nombreuses pathologies cérébrales. Cependant, des pathologies chroniques nécessitent une administration prolongée, ce qui entraîne des effets secondaires encore mal évalués. Une meilleure stratégie serait de réguler cette voie énergétique alternative, en la stimulant, mais seulement lorsque c est nécessaire. Nous avons exploré cette possibilité dans le modèle MPTP murin de la maladie de Parkinson, en utilisant la pantéthine, pro-vitamine B5, thiol largement répandu dans le monde vivant. Ce choix est dicté par le fait que sa forme réduite, la pantéthéine, constitue la partie active du CoA et donc constitue un cofacteur nécessaire au métabolisme des lipides, en général, et à la -oxydation des acides gras, en particulier. Nous montrons que l activité 3-hydroxyacyl-CoA dehydrogenase (HAD), qui catalyse l oxydation de 3-hydroxybutyryl-CoA en acétoacétyl-CoA, est altérée suite à l administration de la neurotoxine, mais elle est restaurée par traitement des souris par la pantéthine. Cela se traduit par l augmentation des taux sanguins de corps cétoniques. Il faut souligner que cette augmentation ne s observe que chez les souris atteintes, et non pas chez les animaux sains. Il en résulte une atténuation des dysfonctions mitochondriales, avec restauration des atteintes dopaminergiques dans l aire nigro-striée. Cette restauration n est que partielle, mais elle est suffisante pour permettre une activité motrice normale. En réalité, cette protection tient sans doute à un effet cumulatif : bien qu étant de faible poids moléculaire et de structure simple, la pantéthine est pluri-fonctionnelle. Elle est notamment anti-inflammatoire (en stimulant la production de GSH et en atténuant la réponse cellulaire aux facteurs pro-inflammatoires), antioxydante, et hypolipidémique. En conclusion, notre travail démontre ainsi la faisabilité d une stratégie thérapeutique qui consiste à viser simultanément différents éléments de la cascade délétère à l origine de la maladie de Parkinson avec, en particulier, restauration du métabolisme énergétique. Nous pensons que cette approche a une portée générale et pourrait s appliquer à d autres pathologies complexes. A partir de l ataxie de Friedreich et la malaria cérébrale, nous apportons quelques éléments qui, bien que préliminaires, confortent cette hypothèse de travail.All the neurodegenerative diseases are to some extent associated with metabolic dysfunctions, characterized by impairment of the glycolytic pathway, the main cerebral energetic source. However, the brain has the ability to use an alternative carbon source for energy production, the lipids. The process, known as fatty acid -oxidation, involves an oxidoreductase superfamily, which uses substrates made of fatty acid linked to Coenzyme A (CoA) via a thioester bond. These enzymes include numerous isoforms, in relation to the highly structural variability of fatty acids. The end products of the process are the ketone bodies -hydroxybutyrate and acetoacetate. When administered to rat or mice, or used in in vitro studies, ketone bodies exert a neuroprotective effect in the context of many diseases. However, as far as chronic diseases are concerned, a long-term administration of these compounds has adverse effects not yet well assessed. Therefore a better strategy would be to regulate the fatty acid -oxidation pathway i.e. to enhance it, however only when necessary. We explored this possibility in the MPTP mouse model of Parkinson s disease, using pantethine, the pro-vitamin B5, a thiol widely spread in the living world. The choice of this compound is dictated by the fact that its reduced form, pantetheine, constitutes the active moiety of CoA. Therefore pantethine/pantetheine is the necessary cofactor for lipid metabolism, including fatty acid -oxidation. We determined 3-hydroxyacyl-CoA dehydrogenase (HAD) activity, which catalyses 3-hydroxybutyryl-CoA oxidation, yielding acetoacetyl-CoA. We found that the enzyme was inhibited in MPTP-intoxicated mice. The activity was restored by pantethine treatment, leading to the increase of circulating levels of ketone bodies. We underline that this rise was observed only in MPTP-intoxicated mice, not in healthy ones. The overall result was mitigation of dopaminergic injury in the nigrostriatal area, in such a way to allow normal mouse motility. In fact, protection is likely to be due to a cumulative effect of the treatment: even though pantethine is a small and simple structure, it displays a multifaceted activity. Among other properties, pantethine is anti-inflammatory (by inducing the enhancement of GSH stores and by inhibiting the activation of cell response to pro-inflammatory factors), antioxidant and hypolipidemic. In conclusion, our work illustrated the feasibility of a therapeutic strategy which targets simultaneously several events in the pathogenic cascade leading to Parkinson s disease, including the restoration of the energy metabolism. Our opinion is that such approach could be applied to other complex diseases. Preliminary studies on Friedreich ataxia and cerebral malaria tend to confirm our hypothesis.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

We report that administration of the low-molecular-weight thiol pantethine prevented the cerebral syndrome in Plasmodium berghei ANKA-infected mice. The protection was associated with an impairment of the host response to the infection, with in particular a decrease of circulating microparticles and preservation of the blood–brain barrier integrity. Parasite development was unaffected. Pantethine modulated one of the early steps of the inflammation–coagulation cascade, i.e., the transbilayer translocation of phosphatidylserine at the cell surface that we demonstrated on red blood cells and platelets. In this, pantethine mimicked the inactivation of the ATP-binding-cassette transporter A1 (ABCA1), which also prevents the cerebral syndrome in this malaria model. However, pantethine acts through a different pathway, because ABCA1 activity was unaffected by the treatment. The mechanisms of pantethine action were investigated, using the intact molecule and its constituents. The disulfide group (oxidized form) is necessary to lower the platelet response to activation by thrombin and collagen. Thio-sensitive mechanisms are also involved in the impairment of microparticle release by TNF-activated endothelial cells. In isolated cells, the effects were obtained by cystamine that lacks the pantothenic moiety of the molecule; however, the complete molecule is necessary to protect against cerebral malaria. Pantethine is well tolerated, and it has already been administered in other contexts to man with limited side effects. Therefore, trials of pantethine treatment in adjunctive therapy for severe malaria are warranted

Theobroma cacao improves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia

International audienceAbstract A gain-of-function mutation in the fibroblast growth factor receptor 3 gene ( FGFR3 ) results in achondroplasia (ACH), the most frequent form of dwarfism. Constitutive activation of FGFR3 impairs bone formation and elongation and many signal transduction pathways. Identification of new and relevant compounds targeting the FGFR3 signaling pathway is of broad importance for the treatment of ACH, and natural plant compounds are prime drug candidate sources. Here, we found that the phenolic compound (-)-epicatechin, isolated from Theobroma cacao , effectively inhibited FGFR3’s downstream signaling pathways. Transcriptomic analysis in an Fgfr3 mouse model showed that ciliary mRNA expression was modified and influenced significantly by the Indian hedgehog and PKA pathways. (-)-Epicatechin is able to rescue mRNA expression impairments that control both the structural organization of the primary cilium and ciliogenesis-related genes. In femurs isolated from a mouse model ( Fgfr3 Y367C/+ ) of ACH, we showed that (-)-epicatechin eliminated bone growth impairment during 6 days of ex vivo culture. In vivo, we confirmed that daily subcutaneous injections of (-)-epicatechin to Fgfr3 Y367C/+ mice increased bone elongation and rescued the primary cilium defects observed in chondrocytes. This modification to the primary cilia promoted the typical columnar arrangement of flat proliferative chondrocytes and thus enhanced bone elongation. The results of the present proof-of-principle study support (-)-epicatechin as a potential drug for the treatment of ACH

Dynamics of particulate organic matter composition in coastal systems: a spatio-temporal study at multi-systems scale

International audienceIn coastal systems, the multiplicity of sources fueling the pool of particulate organic matter (POM) leads to divergent estimations of POM composition. Eleven systems (two littoral systems, eight embayments and semi-enclosed systems and one estuary) distributed along the three maritime façades of France were studied for two to eight years in order to quantify the relative contribution of organic matter sources to the surface-water POM pool in coastal systems. This study was based on carbon and nitrogen elemental and isotopic ratios, used for running mixing models. The POM of the estuary is dominated by terrestrial material (93% on average), whereas the POM of the other systems is dominated by phytoplankton (84% on average). Nevertheless, for the latter systems, the POM composition varies in space, with 1) systems where POM is highly composed of phytoplankton (≥ 93%), 2) systems characterized by a non-negligible contribution of benthic (8 to 19%) and/or riverine (7 to 19%) sources, and 3) the Mediterranean systems characterized by the contribution of diazotroph organisms (ca. 14%). A continent-to-ocean gradient of riverine and/or benthic POM contribution is observed. Finally, time series reveal 1) seasonal variations of POM composition, 2) differences in seasonality between systems, and 3) an inshore-offshore gradient of seasonality within each system that were sampled at several stations. Spatial and seasonal patterns of POM composition are mainly due to local to regional processes such as hydrodynamics and sedimentary hydrodynamic (e.g. resuspension processes, changes in river flows, wind patterns influencing along-shore currents) but also due to the geomorphology of the systems (depth of the water column, distance to the shore). Future studies investigating the link between these forcings and POM composition would help to better understand the dynamics of POM composition in coastal systems