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

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

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

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

Critical role for prokineticin 2 in CNS autoimmunity

Objective: To investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involved in multiple biological functions including immune modulation, in CNS autoimmune demyelinating disease. Methods: We investigated the expression of PK2 in mice with experimental autoimmune encephalo- myelitis (EAE), the animal model of multiple sclerosis (MS), and in patients with relapsing-remitting MS. We evaluated the biological effects of PK2 on expression of EAE and on development of T-cell response against myelin by blocking PK2 in vivo with PK2 receptor antagonists. We treated with PK2 immune cells activatedagainst myelinantigen toexplore the immune-modulating effectsofthis peptide in vitro. Results: Pk2 messenger RNA was upregulated in spinal cord and lymph node cells (LNCs) of mice with EAE. PK2 protein was expressed in EAE inflammatory infiltrates and was increased in sera during EAE. In patients with relapsing-remitting MS, transcripts for PK2 were significantly increased in peripheral blood mononuclear cells compared with healthy controls, and PK2 serum concentrations were significantly higher. A PK2 receptor antagonist prevented or attenuated established EAE in chronic and relapsing-remitting models, reduced CNS inflammation and demy- elination, and decreased the production of interferon (IFN)- g and interleukin (IL)-17A cytokines in LNCs while increasing IL-10. PK2 in vitro increased IFN- g and IL-17A and reduced IL-10 in splenocytes activated against myelin antigen. Conclusion: These data suggest that PK2 is a critical immune regulator in CNS autoimmune demyelination and may represent a new target for therapy