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

Abstract

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.

Pantethine Alters Lipid Composition and Cholesterol Content of Membrane Rafts, With Down‐Regulation of CXCL12‐Induced T Cell Migration

“…Therefore, in spite of its simple linear structure, this well‐tolerated low‐molecular‐weight compound displays a large array of mechanisms and functions that make it a very useful tool for cellular investigation and therapeutic intervention. Pantethine addresses essential cellular pathway, however, with few side effects since, as shown in the MPTP model of Parkinson's disease, it moderates pathological but not physiological processes (Cornille et al, ).…”

“…Unless otherwise mentioned, cells were cultured in the presence of pantethine (0.5 or 1 mM) or pantetheine (1 mM) for 18 h; previous ex vivo treatments showed that maximal cellular effects were obtained under these conditions without side effects (Penet et al, ; Cornille et al, ). Pantethine has been also used at a lower concentration, however, with a longer incubation time (48 h).…”

“…These functions should be finely modulated, since their disturbance can lead to chronic inflammation and other diseases (Gerard and Rollins, ; Moser and Loetscher, ). We have previously shown that the treatment of mice by pantethine attenuates brain perivascular inflammation and protects the blood–brain barrier (BBB) in the cerebral syndrome associated with malaria (Penet et al, ); moreover, it promotes the transition between carbohydrate and lipid utilization for energy production in the diseased brain (Cornille et al, ). Here we looked at its effects on the chemokine stromal‐derived factor‐1α (SDF‐1α/CXCL12) and its G‐protein‐coupled receptor CXCR4.…”

SILEC: a protocol for generating and using isotopically labeled coenzyme A mass spectrometry standards

“…We have demonstrated this by adding propionate to generate propionyl-CoA, but can be extended to other lower-abundance CoA species, such as by adding β-hydroxybutyrate to generate β-hydroxybutyryl-CoA (Fig. 5), an important intermediate in fatty acid oxidation and ketogenesis 64,65 . In addition, cells can be subjected to different biological perturbations or toxicological insults to increase and decrease particular CoA species or to generate xenobiotic-CoA adducts such as menadione-CoA (Fig.…”

The Energy Crisis in Parkinson’s Disease: A Therapeutic Target

“…Moreover, pantethine circumvented the impairment of fatty acid β-oxidation in rat liver mitochondria and microvessels of the brain (Morisaki et al, 1983). It has been shown recently that pantethine mitigated MPTP neurotoxicity in the mouse via the enhancement of fatty acid β−oxidation, leading to increased levels of circulating ketone bodies and improved mitochondrial function (Cornille et al, 2010). In addition, pantethine attenuates MPTPinduced neuroinflammation, as shown by reduced expression of macrophage antigen-1 (MAC-1), a critical trigger of microglial activation associated with neurodegeneration (Pei et al, 2007) (Fig.…”