The effects of an increase in body temperature per se on the lactate and pyruvate concentrations of the arterial blood, muscle venous blood, sagittal sinus blood, and cerebrospinal fluid were determined. Paralysed anesthetized dogs with near normal arterial pH and PC0(2) values were ventilated with a 50% 0(2), 50% N(2) mixture and heated to a temperature of 42°C and maintained at this temperature for a period of 2 hours. During hyperthermia a slight increase in lactate and pyruvate was observed in the arterial blood. However, this was not statistically significant. Also a slight increase in the concentration of these substances occurred in the muscle venous blood and sagittal sinus blood. This change, however, was parallel to that observed in the arterial blood. The lactate-pyruvate ratio of the arterial blood, muscle venous blood and sagittal sinus blood did not show any significant change and thus no increase in anaerobic processes was detected during the hyperthermic period. On the other hand the cerebrospinal fluid lactate and pyruvate increased significantly throughout the hyperthermic period but maintained a constant lactate-pyruvate ratio. The results indicate that the increase of lactate and pyruvate in the cerebrospinal fluid are a result of an increased rate of aerobic glycolysis. The fact that the increases observed in the cerebrospinal fluid lactate and pyruvate were not reflected in the cerebral venous blood indicates lactate and pyruvate may have difficulty in diffusing across the blood brain barrier and cerebral venous blood is thus a poor index of cerebral lactate and pyruvate changes. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Au cours de ces travaux de thèse, une voie de synthèse de différentes cyclopropylamines a été développée. Leur fonctionnalisation a ensuite été mise en œuvre à l’aide de réactions de métallation ou de couplages croisés catalysés au palladium. Les cyclopropylamines ainsi fonctionnalisées furent alors soumises à des conditions de cyclisation dans le but d’obtenir tout ou partie d’une structure 14-azastéroïde. Si notre modèle, dont la synthèse s'est construite autour d’une aniline, nous a permis d'obtenir la structure des cycles B, C et D d'un 14-azastéroïde, nous n'avons pas été en mesure d'obtenir la structure dans sa totalité en partant d'une naphtylamine. Nous avons cependant dans ce cas obtenu un arrangement original pentacyclique comportant un motif cyclobutane. Nous avons enfin réalisés des travaux sur des réactions de type condensation, principalement entre divers dérivés d'aniline et le pyruvate d'éthyle. Lors des résultats préliminaires, nous avons cette fois encore majoritairement obtenu des structures comportant un motif cyclobutane et non celles se rapprochant des azastéroïdes. / In the course of this thesis, a method to synthesize new cyclopropylamines was developed. Their functionalization was then implemented using metallation reactions or palladium catalysed cross-coupling reactions. The functionalized cyclopropylamines were then subjected to cyclization conditions in order to obtain all or part of a 14-azasteroid structure. Our synthetic model, which was built around an aniline moiety, allowed us to obtain the structure of the B, C, and D rings of a 14-azasteroid. Unfortunately, when this strategy was applied to synthesize the complete tetracyclic backbone of the 14-azasteroid from a naphthylamine, the reaction failed to give the same results. We have however in this case reached an original pentacyclic framework containing a cyclobutane motif. Finally, we studied condensation-type reactions between various derivatives of aniline and ethyl pyruvate toward synthesis of the desired structure. Preliminary results show formation of structures with a cyclobutane motif.

Au cours de ces travaux de thèse, une voie de synthèse de différentes cyclopropylamines a été développée. Leur fonctionnalisation a ensuite été mise en œuvre à l'aide de réactions de métallation ou de couplages croisés catalysés au palladium. Les cyclopropylamines ainsi fonctionnalisées furent alors soumises à des conditions de cyclisation dans le but d'obtenir tout ou partie d'une structure 14-azastéroïde. Si notre modèle, dont la synthèse s'est construite autour d'une aniline, nous a permis d'obtenir la structure des cycles B, C et D d'un 14-azastéroïde, nous n'avons pas été en mesure d'obtenir la structure dans sa totalité en partant d'une naphtylamine. Nous avons cependant dans ce cas obtenu un arrangement original pentacyclique comportant un motif cyclobutane. Nous avons enfin réalisés des travaux sur des réactions de type condensation, principalement entre divers dérivés d'aniline et le pyruvate d'éthyle. Lors des résultats préliminaires, nous avons cette fois encore majoritairement obtenu des structures comportant un motif cyclobutane et non celles se rapprochant des azastéroïdes.

Aging is a multifaceted process of accumulation of damage and waste in cells and tissues; age-related changes in mitochondria and in respiratory metabolism have the focus of aging research for decades. Studies of aging in nematodes, flies and mammals all revealed age-related decline in respiratory functions, with somewhat controversial causative role. Here we investigated age-related changes in respiration rates, lactate/pyruvate ratio, a commonly used proxy for NADH/NAD+ balance, and mitochondrial membrane potential in 4 genotypes of an emerging model organism for aging research, a cyclic parthenogen Daphnia magna. We show that total body weight-adjusted respiration rate decreased with age, although this decrease was small in magnitude and could be fully accounted for by the decrease in locomotion and feeding activity. Neither total respiration normalized by protein content, nor basal respiration rate measured in anaesthetized animals decreased with age. Lactate/pyruvate ratio and mitochondrial membrane potential (∆Ψ) showed no age-related changes, with possible exceptions of ∆Ψ in epipodites (excretory and gas exchange organs) in which ∆Ψ decreased with age and in the optical lobe of the brain, in which ∆Ψ showed a maximum at middle age. We conclude that actuarial senescence in Daphnia is not caused by a decline in respiratory metabolism and discuss possible mechanisms of maintaining mitochondrial healthspan throughout the lifespan.