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

Lithostathine, the Presumed Pancreatic Stone Inhibitor, Does Not Interact Specifically with Calcium Carbonate Crystals

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Pantethine Down-Regulates Leukocyte Recruitment and Inflammatory Parameters in a Mouse Model of Allergic Airway Inflammation

International audienceBackground: Migration of leukocytes into airways is the hallmark of allergic asthma. The aim of this study was to target the pathological process using pantethine, a pleiotropic natural compound which has been recently shown to down-regulate chemokine-driven T cell migration.& para;& para;Material/Methods: Mice were sensitized to the Leishmania LACK antigen, then treated or not treated with pantethine and exposed to LACK or saline aerosol. After sacrifice of the animals, cells in the bronchoalveolar lavage were analyzed and inflammatory parameters were determined to evaluate inflammation seriousness.& para;& para;Results: As compared to untreated animals, pantethine-treated animals displayed a moderated response to the allergen, as documented by decreased infiltration of inflammatory cells (all types), in addition to reduced levels of lung Th2 cytokines and circulating LACK-specific IgE.& para;& para;Conclusions: These data reveal the potential therapeutic importance of pantethine to moderate allergic asthma pathology. The compound has been previously shown to exert a broad range of protective activity in animals and in humans, with few or no adverse effects

What function for human lithostathine?: structural investigations by three-dimensional structure modeling and high-resolution NMR spectroscopy

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Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer's disease: Alleviation by pantethine

International audienceAstrocytes play critical roles in central nervous system homeostasis and support of neuronal function. A better knowledge of their response may both help understand the pathophysiology of Alzheimer's disease (AD) and implement new therapeutic strategies. We used the 5xFAD transgenic mouse model of AD (Tg thereafter) to generate astrocyte cultures and investigate the impact of the genotype on metabolic changes and astrocytes activation. Metabolomic analysis showed that Tg astrocytes exhibited changes in the glycolytic pathway and tricarboxylic acid (TCA) cycle, compared to wild type (WT) cells. Tg astrocytes displayed also a prominent basal inflammatory status, with accentuated reactivity and increased expression of the inflammatory cytokine interleukin-1 beta (IL-1β). Compensatory mechanisms were activated in Tg astrocytes, including: i) the hexose monophosphate shunt with the consequent production of reducing species; ii) the induction of hypoxia inducible factor-1 alpha (HIF-1α), known to protect against amyloid-β (Aβ) toxicity. Such events were associated with the expression by Tg astrocytes of human isoforms of both amyloid precursor protein (APP) and presenilin-1 (PS1). Similar metabolic and inflammatory changes were induced in WT astrocytes by exogenous Aβ peptide. Pantethine, the vitamin B5 precursor, known to be neuroprotective and anti-inflammatory, alleviated the pathological pattern in Tg astrocytes as well as WT astrocytes treated with Aß. In conclusion, our data enlighten the dual pathogenic/protective role of astrocytes in AD pathology and the potential protective role of pantethine

Pantethine alters lipid composition and cholesterol content of membrane rafts, with down-regulation of cxcl12-induced t cell migration

Pantethine, a natural low-molecular-weight thiol, shows broad activity in a large range of essential cellular pathways. It has been long known as a hypolipidemic and hypocholesterolemic agent. We showed recently that it exerts a neuroprotective action in mouse models of cerebral malaria and Parkinson's disease through multiple mechanisms. In the present study we looked at its effects on membrane lipid rafts that serve as platforms for molecules engaged in cell activity, therefore providing a target against inappropriate cell response leading to chronic inflammation. We found that pantethine-treated cells showed a significant change in raft fatty acid composition and cholesterol content, with ultimate downregulation of cell adhesion, CXCL12-driven chemotaxis and transendothelial migration of various T cell types, including human Jurkat cell line and circulating effector T cells. The mechanisms involved include the alteration of the following: i) CXCL12 binding to its target cells; ii) membrane dynamics of CXCR4 and CXCR7, the two CXCL12 receptors; iii) cell redox status, a crucial determinant in the regulation of the chemokine system. In addition, we considered the linker for activation of T cells (LAT) molecule to show that pantethine effects were associated with the displacement from the rafts of the acylated signaling molecules which palmitoylation level was reduced. In conclusion, the results presented here, together with previously published findings, indicate that, due to its pleiotropic action, pantethine can down-regulate the multifaceted process leading to pathogenic T cell activation and migration

Correction: Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer's disease: Alleviation by pantethine.

[This corrects the article DOI: 10.1371/journal.pone.0175369.]

Molecular hydrogen attenuates radiation-induced nucleobase damage to DNA ă in aerated aqueous solutions

International audiencePurpose: The main aim of the present study is to gain mechanistic ă insights into the modulating effect of molecular hydrogen on the ă -radiation-induced alteration pathways of DNA nucleobases.Materials and ă methods: Aerated aqueous solutions of calf thymus DNA were exposed to a ă Co-60 source at doses ranging from 0 to 55Gy under normoxic conditions, ă in the presence or not of 0.7MPa hydrogen or helium. The measurement of ă several modified bases was performed using HPLC associated with ă electrospray ionization tandem pass spectrometry (HPLC-ESI-MS/MS). ă Bleaching of aqueous solutions of p-nitrosodimethylaniline (p-NDA) ă solutions was also used to allow the quantification of hydroxyl radical ă (center dot OH) formation.Results:pNDA bleaching was significantly ă reduced in the presence of hyperbaric hydrogen. This is undoubtedly due ă to (OH)-O-center dot scavenging by H-2 since, under the same conditions, ă He had no effect. Similarly, base alterations were significantly reduced ă in the presence of hydrogen, as compared to controls under normal ă atmosphere or in the presence of helium. The relative proportions of ă modified nucleobases were not changed, showing that the only effect of ă H-2 is to scavenge (OH)-O-center dot without exhibiting reducing ă properties.Conclusions: Our findings demonstrate that H-2 exerts a ă significant protection against radiation-induced DNA base damage in ă aqueous solutions, (OH)-O-center dot scavenging being the only mechanism ă involved