Thesis (M. Sc.)-- Springfield College, 2005. / Bibliography: leaves 89-94.

Thesis (M.S.)--Springfield College, 2005. / Includes bibliographical references. Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Pantethine, a precursor of coenzyme A, has been shown to reduce serum cholesterol levels in hypercholesterolemic rabbits. The enzyme pantetheinase rapidly hydrolyzes pantethine to the vitamin pantothenic acid and the amino thiol cysteamine. This study was designed to compare the effect of cysteamine and pantothenate supplementation with that of pantethine on hypercholesterolemic rabbits. New Zealand white rabbits were fed a 0.5% cholesterol diet for 5 weeks; treatment groups received only the high cholesterol diet (control), or a high cholesterol diet supplemented with 1% pantethine, or an equimolar amount of pantothenic acid or cystamine (the disulfide of cysteamine). Blood samples were drawn weekly and total serum cholesterol levels analyzed enzymatically. Pantethine and cystamine both significantly reduced serum cholesterol levels (p < 0.05); pantothenic acid had no effect. Separation of serum lipoproteins using a preparative ultracentrifuge showed an increase in very low density, intermediate density and low density lipoproteins. A second experiment was conducted to compare the effect of cystamine with other small thiols; the protocol was similar to the first experiment with treatment groups consisting of a high cholesterol control, cystamine, cystine or 2,hydroxyethyl disulfide. There was no significant reduction in serum cholesterol levels between treatment groups, although the cystamine supplemented group tended to be lower than the other groups.

Nous avons exploré les altérations cérébrales liées à l’âge, dans des conditions physiologiques ou pathologiques (maladie d’Alzheimer), à partir de deux modèles murins, SAM-P8 (souris à sénescence accélérée) et 5xFAD..Dans les deux cas, les animaux montrent des signes de neuroinflammation avec libération de la principale cytokine pro-inflammatoire IL-1β. Ces troubles sont sans conteste d’origine endogène, puisqu’ils n’ont pas été observés chez les témoins. Il faut souligner que les astrocytes 5xFAD ont été prélevés chez des nouveau-nés et par conséquent leur état inflammatoire signifie que la neuroinflammation est une des toutes premières manifestations de la pathologie, bien en amont de la formation des plaques amyloïdes.Dans toute pathologie complexe, les troubles sont la résultante d’un ensemble de processus pathologiques. Nous avons donc recherché les effets protecteurs de la pantéthine. Cette molécule naturelle de faible taille moléculaire, a démontré une action de protection dans plusieurs pathologies cérébrales. Dans la présente étude, le traitement des astrocytes et des souris par la pantéthine modère les altérations observées dans les deux modèles. En particulier, le traitement stimule l’expression de HIF-1α, via son action sur le cycle de Krebs et sur l’activité du protéasome.En conclusion, nous avons montré que la neuroinflammation est à la base du processus pathologique conduisant à la maladie d’Alzheimer et qu’elle se manifeste également au cours du vieillissement. La pantéthine est donc susceptible de contrecarrer le développement de la maladie, comme de tempérer les effets du vieillissement cérébral. / We used two mouse models to explore the age-related cerebral alterations, under physiological and pathological conditions (Alzheimer’s disease), i.e. senescence accelerated SAM-P8 and transgenic 5xFAD mice.In the two models, mice showed signs of neuroinflammation with release of the major inflammatory cytokine IL-1β. Such events were undoubtedly of endogenous origin as they did not occur in the controls. It should be underlined that, since 5xFAD astrocytes were collected in newborns, their inflammatory status means that neuroinflammation is a very early step of Alzheimer’s disease pathological process, upstream of β-amyloid accumulation.Since in a complex disease such as Alzheimer’s brain insults result not from a single cause but from multiple pathological processes, we explored the protective effects of pantethine, a low-molecular-weight, multifunctional agent which has been shown to exert protective effects in several neurodegenerative diseases through multiple convergent mechanisms. In our study, pretreatment of astrocytes and treatment of mice with pantethine moderated age-related alterations. Moreover, it enhanced HIF-1α expression via the modulation of the Krebs’ cycle and proteasomal activities. In addition, a genome wide transcriptomic analysis from hippocampus samples of 5xFAD mice showed that pantethine attenuated most of gene overexpression in transgenic vs WT mice.In conclusion, we found that neuroinflammation lays at the root of Alzheimer’s disease pathological process and is also present in aging mice. Pantethine, this natural and well-tolerated compound could therefore prevent the disease development and temper the deleterious aging effects.