We showed that the neurotoxin 2'-methyl-MPTP inhibited L-3-hydroxybutyryl-CoA dehydrogenase activity and caused a concomitant fall of circulating levels of the product of the reaction, acetoacetate (ACA). These alterations were avoided by pantethine treatment. The protective effect of pantethine was associated with the enhancement of GSH synthesis, restoration of mitochondrial function, i.e. complex I activity, ATP synthesis and oxygen consumption, leading to a protection against dopaminergic injury.
KBs are produced by hepatocytes and are transported to the tissues, including the brain; astrocytes are also ketogenic, although to a lesser extent however . In agreement, we found that dehydrogenase activity is two-orders of magnitude higher in the liver than in the brain, and circulating KB levels correlate with enzyme activity of the liver. We observed that injection of the neurotoxin induced, in both brain and liver, a decrease of dehydrogenase activity, which was restored by pantethine treatment. These findings may be compared with published data on L-3-hydroxyacyl-CoA dehydrogenase type II/amyloid binding alcohol dehydrogenase (HADHII/ABAD). The enzyme is downregulated in PD patients and in the mouse, on days 2 to 7 after MPTP injection. Conversely, transgenic mice with increased expression of human HADHII/ABAD are significantly more resistant to MPTP; overexpression of the enzyme mitigates MPTP-induced impairment of oxidative phosphorylation and ATP production . Thus the changes of dehydrogenase activity that we observed following MPTP injection and pantethine treatment may reflect changes in the amount of the enzyme.
Pantethine is metabolized in vivo, yielding mainly pantetheine, cysteamine, pantothenic acid and 4'-phosphopantetheine (4'-PP) . All these derivatives may well be involved in the effects that we observed after treatment with pantethine. The treatment increased the GSH concentration, which is likely to be mediated by the increase of intracellular levels of L-cysteine via disulfide exchange reactions. Free cysteine is available to several pathways, including formation of mixed disulfides, and synthesis of glutathione . The maintenance of normal GSH levels is essential for NADH-ubiquinone oxido-reductase (complex I) activity since the complex I is thiol-regulated [13, 40, 41]. Accordingly, we found that, when applied to isolated mitochondria, the reduced form pantetheine was able to preserve complex I activity, and therefore to maintain complex I redox status; the oxidized form pantethine did not. It should be underlined that GSH and CoA levels, as well as complex I activity and ATP production are interdependent and their interactions remain to be clarified [42, 43].
Our main finding is that the administration of pantethine to 2'-methyl-MPTP intoxicated mice stimulates fatty acid β-oxidation and increases circulating KB levels.
This effect is specific for pantethine and was not observed with cystamine. This may reflect the fact that pantetheine constitutes the active moiety of CoA. Not only CoA-fatty acid thioesters but also pantetheine- and 4'PP-fatty acid thioesters are acceptable substrates for HAD. In comparison, cysteamine is a too small an entity; the HAD Km value is 125 fold higher for acyl-cysteamine than for acyl-pantetheine . The thiol group and the pantoic acid moiety (2,4-dihydroxy-3-dimethyl butyric acid) of pantetheine play a central role in enzyme binding [44, 45]. These elements do not occur in either pantothenic acid or cysteamine, respectively. Accordingly, under our experimental conditions, these two compounds were unable to enhance either dehydrogenase activity or circulating levels of KB (data not shown). Pantethine also displays anti-inflammatory activity in inhibiting the activation of the cellular response to pro-inflammatory factors, as we reported earlier .
In summary, treatment with pantethine reproduces the effects of KB administration and ketogenic diets with however several advantages. First, the stimulation of KB synthesis is a rational way to enhance KB levels. Second, long-term administration of high fat diets has detrimental effects  that could be circumvent by the hypolididemic properties of pantethine. Third, pantethine has apparently no effects on circulating ACA levels under normal conditions, meaning that it could act "on demand" only.