Le cerveau humain est un organe très métaboliquement actif. Cet énorme besoin énergétique l’expose à un risque accru de détérioration causée par un dérèglement de ce métabolisme. Dans la phase précoce de la maladie d’Alzheimer, un hypométabolisme cérébral du glucose est observé. Cette carence énergétique serait à l’origine des détériorations observée lors du développement de cette maladie. Le cerveau a accès à une autre source endogène d’énergie : les cétones. Les cétones sont particulièrement importantes pour le cerveau puisqu’il ne possède pas la capacité d’utiliser les acides gras comme source énergétique à l’instar des autres organes. Les cétones sont issues de la β-oxydation hépatique des acides gras. Ils sont produits en situation de jeûne lorsque les niveaux circulants de glucose et d’insuline sont bas. Les cétones se sont déjà montré efficaces dans le traitement de divers troubles neurologiques comme l’épilepsie. Par contre, outre les diètes cétogènes et le jeûne prolongé, il n’existe pas de traitement efficace pour maintenir une cétonémie modérée chez l’adulte. Le métabolisme énergétique cérébral en situation de cétose modérée reste encore mal compris dans cette population. Les travaux de cette thèse se sont donc concentrés à étudier la possibilité d’une combinaison d’approche nutritionnelle et pharmacologique afin de stimuler la cétogenèse chez l’adulte. Ils ont aussi exploré les changements de métabolisme cérébral chez l’adulte durant une cétose modérée. L’objectif de la première étude était d’étudier le potentiel du bezafibrate à stimuler la cétogenèse induite par une supplémentation en triglycérides de moyennes chaînes (MCT). Cette première étude a démontré que le bezafibrate avait peu d’effet sur la stimulation de la cétogenèse induite par les MCT et que le facteur limitant dans cette stimulation était donc la disponibilité des substrats et non la capacité cétogène des cellules hépatiques. L’objectif de la seconde étude était d’étudier les changements de capture des cétones et du glucose au cerveau durant un état de cétose modérée chez l’adulte. Les résultats de cette deuxième étude ont montré que la capture des cétones au cerveau est directement proportionnelle à leur concentration plasmatique. Cette étude a aussi démontré que la capture cérébrale des cétones était directement reliée à leur concentration plasmatique alors que la capture cérébrale du glucose est modulée par les besoins énergétiques du cerveau. Une stimulation cétogénique chez des personnes atteintes de déclin cognitif pourrait donc aider à rétablir la balance énergétique et ralentir l’apparition des symptômes chez ces personnes mais cet effet devra être étudié dans une étude ultérieure. / Abstract : The human brain is the most metabolically active organ of the body. This high need for energy exposes it to an increase risk in case of hypometabolism. Such a glucose hypometabolism is seen during the early stages of Alzheimer’s disease. This factor is believed to be one of the cause of the disease. Ketones are the main alternate substrate for the human brain. Ketones are particularly important since, unlike other organs, the brain can not use fatty acids as alternative fuel. Ketones are mainly produce through β-oxidation of fatty acid by the liver. This happens mainly during fasting when circulating levels of glucose and insulin are low. Studies have shown that ketones can have a therapeutic effect in a variety of neurological diseases, mainly epilepsy and Alzheimer’s disease. Nevertheless, apart from ketogenic diet and prolonged fasting, there is currently no effective ways to induce and maintain moderate ketosis in adults. Brain energy metabolism under moderate ketosis remains also misunderstood in this population. This thesis aimed look at the effect of a combination of a pharmacological treatment and a nutritional supplementation to induce moderate sustain ketosis in adults. It also studied the effect of a moderate ketosis on brain energy metabolism in adults. The aim of the first study was to study the effect of a pharmacological treatment, bezafibrate, on the potentiation of the ketogenic effect induced by a medium-chain triglycerides (MCT) supplementation. The results of this study that bezafibrate had little effect on the ketosis induced by a MCT supplementation and, therefore, that the limiting factor in human ketosis was not the liver cells capacity to produce ketones but the availability of substrates for ketogenesis. The aim of the second study was to study the impact of a nutritional moderate ketosis on brain glucose and ketone uptake. The results of this study showed a direct correlation between brain ketone uptake and plasma ketone concentrations. This study also showed that brain ketone uptake is regulated by blood ketone concentration whereas brain glucose uptake is regulated by the brain energy needs. Further studies should then look if such a moderate ketosis induced in cognitively impaired patients could re-equilibrate the energy balance in the brain and then slow the apparition of clinical symptoms in this population.

Depuis maintenant plus de 30 ans, il est reconnu qu’au début de la maladie d’Alzheimer, le cerveau utilise moins bien le glucose, son principal carburant. Cependant, ce problème énergétique précoce dans la maladie semblerait limité au glucose et ne concernerait pas un autre carburant, celui-ci dérivé des gras, les cétones. Ces dernières sont produites par le corps après un exercice physique d’intensité modérée. Leur production est également stimulée avec la prise de suppléments alimentaires à base d’huile de noix de coco, un aliment riche en triglycérides de moyennes chaînes (MCT). La capture des cétones au cerveau augmente proportionnellement à leur concentration plasmatique. Ainsi, des conditions élevant la cétonémie augmentent aussi la capture cérébrale des cétones. Par conséquent, l’élévation de l’apport en cétones pourrait constituer une approche novatrice qui permettrait de potentiellement ralentir le développement de la maladie d’Alzheimer. Notre objectif général était d’optimiser le type de supplément MCT à utiliser afin d’élever la cétonémie de manière aigüe et, en second lieu, d’employer ce dernier en combinaison avec une seconde stratégie cétogène, l’exercice physique de type aérobie (EA). Lors de la première phase de ce projet, l’effet cétogène de différents produits alimentaires dérivant de l’huile de noix de coco (acide caprylique [C8], acide caproïque [C10], mélange de MCT typique [C8+C10]) était comparé chez 9 participants jeunes sains. Des échantillons sanguins étaient récoltés toutes les 30 min pendant 8 h. Lors de la seconde phase, le potentiel cétogène de la combinaison d’EA à une supplémentation MCT était évalué chez 10 femmes âgées saines pendant 5 jours. Les cétones plasmatiques sous ces différentes conditions étaient mesurées. Lors de cette étude, le C8 était le produit le plus cétogène testé suivi du supplément C8+C10. L’huile de noix de coco n’a pas induit une cétonémie plus élevée qu’un 8 h sans MCT. De plus, l’ajout de 5 jours d’EA a potentialisé la cétonémie observée suite à la prise de MCT C8+C10 seul. Ainsi, la combinaison de stratégies cétogènes, tant au niveau de la diversité des molécules utilisées ou des stratégies cétogènes employées, permet d’augmenter la présence de cétones dans le sang. / Abstract : Brain glucose consumption deteriorates with age, a situation that worsens with the onset of Alzheimer's disease. However, this early energy problem in the disease is limited to glucose and does not affect brain ketone uptake. Ketones are the main alternative fuel for the brain when glucose concentrations are decreased. They are produced endogenously after moderate aerobic exercise (AE) or with a medium chain triglyceride (MCT) exogenous supplement. Ketone brain uptake increases in proportion to their plasma concentration. Thus, providing a daily ketogenic fuel could help support brain energy needs during aging. Our aim was to optimize the type of MCT to use in a ketogenic supplementation and to combine this supplement with another ketogenic strategy, AE. In the first phase of this project, the acute ketogenic effect of products derived from coconut oil was compared. Nine healthy adults took various MCT supplements (coconut oil, caprylic acid [C8], capric acid [C10], classic MCT mix [C8+C10]). Blood was sampled every 30 min over 8 h. In the second phase, we evaluated the acute ketogenic potential of the combination of AE and MCT supplementation. Ten healthy older women took C8+C10 MCT supplement for 5 days combined with a 5-days AE program. Automated spectrophotometric assays where used to measure plasma ketones under these different conditions. Our results show that in this 8 h experimental design, C8 was the most ketogenic MCT followed by C8+C10. Coconut oil alone did not induce more net ketosis than an 8 h visit with no added MCT. Furthermore, the combination of AE and MCT supplementation enhanced the ketogenic response over 4 h compared to the control day. Thus, the combination of ketogenic strategies, both in terms of the diversity of the molecules or the ketogenic strategy employed, makes it possible to increase the presence of ketones in the blood.

Thesis (MScAgric)--Stellenbosch University, 2008. / ENGLISH ABSTRACT: Different substances were evaluated and compared to an antibiotic, in terms of their effect on nitrogen - and amino acid digestibilities. Two digestibility trials and one performance trial were conducted. Trials one and two apparent nitrogen (AND)- and amino acid (AAD) digestibilities were determined from digesta collected at the terminal ileum (ileal digestibility method). In Trial 3 the substances were evaluated in terms of their potential to improve production performance. Broilers were fed a maizesoya based diet throughout the three trails. In the first trial, garlic and a commercial prebiotic (Bio-Mos®), were tested and compared in terms of AND and AAD, to an antibiotic (doxycyclin, Doxyvete-SOS). A starter and finisher diet were fed as either mash or pellets. The garlic was included at 8g/kg, 13g/kg and 18g/kg to the starter and finisher diets. Bio-Mos® was added at 1g/kg, 2g/kg and 3g/kg to the starter diet, and 0.5g/kg, 1g/kg and 1.5g/kg to the finisher diet. The doxycyclin was added at 0.3 g/kg. None of the treatments had any beneficial effects in terms of AND. Feeding a pellet seem to have some negative effects in terms of AND. In general most of the treatments did not show any improvement in AAD at any determination period (day 21, 28 or 35). At day 21 and day 35, the mash diet supplemented with 18g/kg garlic had a negative effect on AAD, when compared to the negative and positive control. It doesn’t seem that feeding either a mash or a pellet had an influence on the effects exerted by the different treatments. In the second trial the influence of Bio-Mos®, a blend of organic acids, probiotics and electrolytes (Acid-Pak 4-way®) and a medium-chain triglyceride (MCT) were evaluated and compared in terms of AAD and AND, to the effect of an antibiotic, doxycyclin. The starter and finisher diets were fed as a mash. Bio-Mos® was included at 1g/kg, 2g/kg, and 3g/kg in the starter diet, and at 0.5g/kg, 1g/kg, 1.5g/kg in the finisher diet, respectively. Acid-Pak 4-way® was included at 0.4g/kg, 1g/kg and 1.6g/kg for both the starter and finisher diets. Medium-chain triglycerides (MCT) were allocated at 3g/kg, 3.6g/kg, 4.2g/kg for the starter diet, and 2.1g/kg, 2.7g/kg and 3.4g/kg for the finisher diet. An antibiotic, doxycyclin, was included at 0.3 g/kg. With AND, no treatment had any significant effect for the entire experimental period. At day 21, the treatment supplemented with MCT (3.4g/kg) had the most significant beneficial effect on AAD, when compared to the negative- and positive controls, as it increased AAD for the majority of the amino acids. The treatment with Acid-Pak 4-way® (1g/kg) had the most significant negative effect on AAD when compared to the positive control. At day 28, the treatments with Bio-Mos® (0.5g/kg and 1.5g/kg) and Acid-Pak 4-way® (0.4g/kg) had the most significant beneficial effect on AAD when compared to the positive control. It increased AAD for more than half of the 17 amino acids evaluated. The treatment supplemented with MCT (2.7g/kg) has shown the most significant negative effect on AAD, when compared to the positive control. In the third trial the effect of Bio-Mos®, Acid-Pak 4-way® and MCT on production performance was evaluated, and compared to the effects of the presence or absence of doxycyclin. Body weight (BW), body weight gain (BWG), feed intake (FI) and feed conversion ratio (FCR) were measured. The starter and finisher diets were fed as a mash. Bio-Mos®, MCT and Acid-Pak 4-way® were included at 3.0g/kg, 4.2g/kg and 1.6g/kg, respectively in the starter and finisher diets. Birds were weighed (per pen) on arrival and on days 7, 14, 21, 28, 35. Feed intake (FI) per pen was measured at days 7, 14, 21, 28 and 35, and mortality was recorded daily. In terms of BWG, Acid-Pak 4-way® had a higher BWG, when compared to the negative control, Bio-Mos® and MCT. It can be concluded that Bio-Mos®, Acid-Pak 4-way®, as well as MCT can be a possible alternatives to antibiotic supplementation. These three treatments did not necessary prove to be more effective than antibiotics, but are definitely competitive alternatives. / AFRIKAANSE OPSOMMING: Verskillende behandelings is geëvalueer en vergelyk met ‘n antimikrobiese produk, in terme van hul uitwerking op stikstof - en aminosuur verteerbaarhede. Twee verteringstudies en produksieprestasie studie is uitgevoer. In die eerste twee studies is die skynbare stikstof (AND)- en aminosuur (AAD) verteringskoöeffisiënte bepaal deur gebruik te maak van digesta wat by die terminale ileum ingesamel is (ileale verteringsmetode). In die derde studie is die produksie prestasie van braaikuikens op ‘n gebalanseerde metaboliseerbare energie (AME) rantsoen, soos beïnvloed deur die verskillende behandelings, geëvalueer. In die eerste studie is knoffel en ‘n kommersiële prebiotikum (Bio-Mos®) geëvalueer en met ‘n antibiotikum (doksisiklien, Doxyveto-SOS) in terme van AND en AAD vergelyk. Beginner- en afrondingsrantsoene is as ‘n meel of pille gevoer. Die knoffel is teen 8g/kg, 13g/kg en 18g/kg in die rantsoen ingesluit. Bio-Mos® is teen 1g/kg, 2g/kg en 3g/kg in die beginner rantsoen en teen 0.5g/kg, 1g/kg en 1.5g/kg in die afrondingsrantsoen, ingesluit. Die antibiotikum is teen 0.3g/kg in beide rantsoene ingesluit. Geen van die behandelings het enige positiewe invloed op AND gehad nie. Deur ‘n verpilde rantsoen te voer het sekere negatiewe invloed op AND gehad. Oor die algemeen het geen behandelings enige positiewe invloed op AAD gehad nie. Op dag 21 en 35 het die insluiting van knoffel teen 18g/kg in ’n meel rantsoen ’n negatiewe invloed op AAD gehad, wanneer dit met die negatiewe- en positiewe kontroles vergelyk is. Dit blyk nie dat om ‘n pil of meel te voer enige invloed op die invloede van die verskillende behandelings gehad het nie. In die tweede studie is Bio-Mos®, ‘n organiese suur (Acid-Pak 4-way®) en ‘n medium-ketting trigliseried (MCT) geëvalueer en met ‘n antbiotikum, doksisiklien (Doxyveto-SOS) in terme van AND en AAD, vergelyk. Beginner- en afrondingsrantsoene is gevoer as ‘n meel. Bio-Mos® is teen 1g/kg, 2g/kg, and 3g/kg in die beginner rantsoen en teen 0.5g/kg, 1g/kg, 1.5g/kg in die afrondingsrantsoen, ingesluit. Acid-Pak 4-way® is teen 0.4g/kg, 1g/kg en 1.6g/kg vir die beginner –en afrondingsrantsoene ingesluit. Die MCT is teen 3g/kg, 3.6g/kg, 4.2g/kg in die beginner rantsoen en teen 2.1g/kg, 2.7g/kg en 3.4g/kg in die afrondingsrantsoen ingesluit. Die antibiotikum is ingesluit teen 0.3g/kg. Geen behandelings het enige betekenisvolle invloed in terme van AND gehad nie. Op dag 21 het MCT (3.4g/kg), in vergelyking met die negatiewe- en positiewe kontrole, die grootste positiewe invloed op AAD gehad. Acid-Pak 4-way® (1g/kg) het, in vergelyking met die positiewe kontrole, ‘n positiewe invloed gehad op AAD. Op dag 28, het Bio-Mos® (0.5g/kg en 1.5g/kg) en Acid-Pak 4-way® (0.4g/kg) die grootste positiewe invloed op AAD gehad. Die behandeling met MCT (2.7g/kg) het die mees negatiewe invloed op AAD gehad. In die derde studie is die insluiting van Bio-Mos®, Acid-Pak 4-way® en MCT getoets om die invloed op braaikuiken produksie prestasie te evalueer, en te vergelyk met die invloed van die insluiting of afwesigheid van ‘n antibiotikum. Liggaamsmassa (BW), liggaamsmassa toename (BWG), voerinname (FI) en voeromsetverhouding (FCR) is gemeet. Beginner- en afrondings rantsoene is gevoer as ‘n meel. Bio-Mos®, MCT en Acid-Pak 4-way® is onderskeidelik teen 3.0g/kg, 4,2g/kg en 1.6g/kg in die rantsoen ingesluit. Die kuikens is met aankoms (per hok) geweeg, asook op dae 7, 14, 21, 28, 35. Voerinname per hok is gemeet op dae 7, 14, 21, 28 en 35. Mortaliteite is daagliks aangeteken. Die insluiting van Acid-Pak 4-way® het in vergelyking met die negatiewe kontrole, Bio-Mos® en MCT insluiting ‘n hoër BWG tot gevolg gehad. Die gevolgtrekking wat gemaak kan word is dat Bio-Mos®, Acid-Pak 4-way® en MCT gebruik kan word as ‘n moontlike alternatief vir antibiotika insluiting. Hierdie drie behandelings was nie noodwending meer effektief as die antibiotika nie, maar het wel bewys dat dit kompeterende alternatiewe is.

Dietary intervention remains a popular, albeit challenging, approach for combating obesity. In recent years, dietary interventions that increase consumption of medium-chain triglycerides (MCT) instead of long-chain triglycerides (LCT) have gained attention. Pre-clinical research has demonstrated that rats fed a high-fat diet (HFD) induce adiposity, but a dietary shift from LCT to MCT suppresses this effect. To date, the extent to which this effect operates via suppressed hyperphagia is not fully understood. In the present study, we sought to determine how consuming a HFD composed of different fat types affects energy intake, adiposity, and hippocampal brain-derived neurotropic factor (BDNF) levels. Rats were assigned to one of four diet groups – rat chow (CHOW), LCT-enriched HFD (LCT-HFD), MCT-enriched HFD (MCT-HFD), or coconut oil-enriched HFD (COCO-HFD), which composes a mixture of LCT and MCT. In Experiment 1, all animals were given <i>ad libitum</i> access to their assigned diet, whereas in Experiments 2 and 3, HFD-subjects were pair-fed to CHOW to prohibit hyperphagia. In Experiments 1 and 2, subjects were aged 20-24 weeks, whereas in Experiment 3, subjects were aged 10-11 weeks. Across experiments, we found that the effect of MCT consumption on suppressing HFD-induced adiposity is causally related to suppressed HFD-induced hyperphagia. Additionally, we failed to detect an effect of HFD consumption on hippocampal BDNF. Therefore, our findings did not support or oppose the hypothesis that MCT consumption attenuates HFD-induced BDNF deficiency. Future studies should focus on determining the causal relationship between MCT consumption, energy expenditure, and HFD-induced adiposity.

Introdução: A doença hepática gordurosa não alcoólica é caracterizada pelo acúmulo hepático de lipídeos, principalmente na forma de triglicerídeos. Devido à atividade inflamatória progressiva pode evoluir para uma forma mais grave, a esteatohepatite não alcoólica. Os ácidos graxos poli-insaturados ômega-3 são associados a efeitos metabólicos positivos para redução da esteatose hepática, no entanto, são mais susceptíveis a peroxidação lipídica. Os triglicerídeos de cadeia média (TCMs) promovem a prevenção do bloqueio da beta-oxidação de ácidos graxos e redução da peroxidação lipídica, no entanto os efeitos na redução da esteatose ainda são controversos. Objetivo: O objetivo do estudo foi avaliar as implicações da dieta hiperlipídica (HL+) com óleo de peixe ou com óleo de TCM no desenvolvimento da esteatose hepática, no perfil de ácidos graxos hepáticos e no estresse oxidativo em ratos. Metodologia: Cinquenta ratos machos da linhagem wistar foram divididos em 5 grupos. Os animais receberam água e comida a vontade durante 45 dias. A adaptação a dieta HL+ foi realizada nos primeiros 15 dias. A composição da dieta do grupo que recebeu somente a gordura animal (HL+GA) era de 50% de gordura animal, e a dieta dos grupos HL+OS, HL+TCM e HL+OP era composta por 35% de gordura animal e 15% de óleo de soja, óleo de TCM e óleo de peixe, respectivamente. Resultados: Todos os grupos que receberam as dietas hiperlipídicas apresentaram maior acúmulo de gordura total e de triglicerídes hepaticos e somente os grupos HL+GA e HL+TCM apresentaram maior acúmulo de colesterol total hepático em relação ao controle. O grupo HL+TCM apresentou maior acúmulo percentual de gordura e um exacerbado acúmulo de triglicerídeos hepáticos em relação aos grupos alimentados com as dietas HL+. A redução do colesterol total sérico foi observada nos grupos HL+TCM e HL+OP, comparados ao controle. A maior incorporação hepática dos ácidos graxos EPA e DHA no grupo HL+OP contribuiu para o aumento do Índice de Peroxibilidade dos ácidos graxos e das substâncias reativas ao ácido tiobarbitúrico livres e totais e para a depleção da vitamina E no fígado. A maior razão AGS/AGPI hepática observada no grupo HL+TCM contribuiu para a preservação dos antioxidantes hepáticos. A alanina aminotransferase, um marcador de dano hepático, apresentou-se aumentada em todos os grupos que receberam as dietas HL+. Conclusões: A dieta hiperlipídica foi eficiente na indução do acúmulo de gordura hepática. O uso do óleo de TCM foi associado a uma maior concentração de lipídeos e preservação dos antioxidantes hepáticos. A dieta hiperlipídica com óleo de peixe foi associada ao aumento significativo na peroxidação lipídica, apesar do menor acúmulo de colesterol e triglicerídeos hepaticos. / Introduction: The Non-alcoholic Fatty liver disease is characterized by hepatic accumulation of lipids, mainly in the form of triglycerides. The disease may progress to a more severe form, the Non-alcoholic steatohepatitis, due to progressive inflammatory activity. Many authors have shown positive metabolic effects associated with the use of polyunsaturated omega-3 fatty acids and reduction in hepatic steatosis. However, these fatty acids are more susceptible to lipid peroxidation. The medium chain triglycerides (MCTs) are able to block beta-oxidation of fatty acids and reduce lipid peroxidation, but the MCT effects in steatosis are still controversial. Objective: The aim of this study was to assess the implications of high-fat diet (HF+) with fish oil or with MCT oil in the development of hepatic steatosis, liver fatty acid profile and oxidative stress markers in rats. Methodology: Fifty wistar male rats were divided into 5 groups. The animals had free access to food and water for 45 days. The first 15 days was dedicated for adaptation to high-fat diet. The HF+AF group received high-fat diet with 50% of animal fat and the other high-fat diets were made with 35% of animal fat plus 15% of other types of fat: soybean oil (HF+SO), MCT oil (HF+MCT) and fish oil (HF+FO). Results: The high-fat groups had higher hepatic total fat and triglycerides accumulation and only the groups HF+AF and HF+MCT had higher accumulation of hepatic cholesterol compared to control. The HF+MCT group had the highest percentage of hepatic fat accumulation and an exacerbated triglyceride accumulation in the liver among HF+ groups. The serum total cholesterol decreased in groups HF+MCT and HF+FO compared with the control group. The highest incorporation of hepatic fatty acids EPA and DHA in the HF+FO group contributed to the increased fatty acids peroxidizability index and total and free hepatic TBARS and depletion of hepatic vitamin E. The biggest ratio SFA/PUFA of liver fatty acids observed in the HF+MCT group contributed to the preservation of hepatic antioxidants. The alanine aminotransferase is a liver damage marker and was increased in all high-fat groups. Conclusions: The high-fat diet was effective to increase the hepatic fat concentration. The consumption of MCT oil can increase the hepatic lipid concentration and hepatic antioxidants. There was a significant increase in hepatic lipid peroxidation in the HF+FO group, although hepatic cholesterol and triglycerides were decreased.

Idebenone is an antioxidant, a synthetic derivative of coenzyme Q10, with several applications, such as neuroprotection. However, this drug has low solubility in water, besides is irritant substance and has chemical instability. Hence, idebenone-loaded nano-organized systems have been developed, such as polymeric nanocapsules (NC). Vegetable oils containing antioxidants such as coconut oil and palm oil can be interesting for the composition of these particles. In this way, the aim of this work was to develop NC suspensions containing different oils as core (palm, coconut or medium chain triglycerides) for delivery of neuroprotective agent idebenone in order to compare the behavior of these systems concerning physico-chemical stability, photostability, controlled release, and conversion to redispersible solid dosage forms (lyophilized products). The nanocapsules were prepared by interfacial deposition of preformed polymer. As the results, it was possible to prepare poly(Ɛ-caprolactone) NC suspensions and palm oil (PO/PCL) or Eudragit® RS100 and coconut oil (OC/EUD) containing idebenone (1.0 mg/mL) with appropriate physico-chemical characteristics. Parameters such as the proportion of aqueous phase/organic phase, type of both surfactant (low HLB) and polymer influenced the optimization of these systems. For comparison, corresponding formulations were prepared with medium chain triglycerides (TCM/PCL or TCM/EUD), using the same conditions. The suspensions had an average diameter between 166 and 216nm, low polydispersity index (0.085 to 0.142), positive or negative zeta potential, depending on the characteristics of the polymer, and high encapsulation efficiency. The maintenance of average particle diameter and low polydispersity index have be verified during stability study (room temperature and exposed or not to light) for 75 days. However, the idebenone content significantly decreased in this period, with influence on the type of polymer. Thereafter, photostability study has shown that the suspensions NC OP/PCL (UVC/UVA) and TCM/PCL (UVA) were able to significantly reduce the degradation of idebenone (content: 53,7-76,1%) compared to an aqueous micellar (content: 31,2-63,1%) dispersion containing the drug. In addition, these systems were able to promoting drug controlled release (t1/2 26 h), without burst effect, showing monoexponential profile (t1/2< 3.0 h for free drug). The lyophilization of suspensions, employing trehalose as soluble carbohydrate, resulted in suitable and redispersible products (content of 96-100%, less than 3.6% moisture; 0.8-1.2 index), presenting several spherical structures, including in colloidal range, featuring the presence of NC in these dried products. In the stability study (room temperature/protection from light and moisture), it was observed that the lyophilized products were able to delay or decrease the degradation of idebenone compared to suspensions of origin, regardless of the both type of polymer (PCL/EUD) and oil (OP/OC/TCM). In conclusion, the developed systems are promising for the controlled release of neuroprotective drug idebenone. / A idebenona é um antioxidante, derivado sintético da coenzima Q10, com várias aplicações, como em neuroproteção. No entanto, este fármaco possui baixa solubilidade em água, potencial irritativo e instabilidade química, fato que tem despertado o interesse em sua associação a sistemas nano-organizados. Dentre estes, destacam-se as nanocápsulas poliméricas (NC). Óleos vegetais, contendo compostos antioxidantes, como óleo de coco e de palma, podem ser interessantes para a composição destas partículas. Neste sentido, o objetivo deste trabalho foi desenvolver suspensões de NC contendo diferentes óleos como núcleo (palma, coco ou triglicerídeos de cadeia média), almejando à veiculação do neuroprotetor idebenona, de forma a comparar o comportamento dos sistemas quanto à estabilidade físico-química, fotoestabilidade, controle de liberação, além da conversão em formas farmacêuticas sólidas redispersíveis (liofilizados). As NC foram preparadas pelo método de deposição interfacial de polímero pré-formado. Conforme os resultados, foi possível preparar suspensões de NC de poli(ε-caprolactona) e óleo de palma (OP/PCL) ou de Eudragit® RS100 e óleo de coco (OC/EUD), contendo idebenona (1,0 mg/mL), com características físico-químicas adequadas, sendo que fatores como proporção das fases aquosa/orgânica, tipo de tensoativo de baixo EHL e de polímero influenciaram a otimização dos sistemas. Para fins comparativos, formulações correspondentes foram preparadas com triglicerídeos de cadeia média (TCM/PCL ou TCM/EUD), empregando as mesmas condições. As suspensões apresentaram diâmetros médios entre 166 e 216 nm, baixos índices de polidispersão (0,085-0,142), potencial zeta positivo ou negativo, dependendo das características do polímero e elevada eficiência de encapsulamento. Quando estas suspensões foram submetidas a estudo de estabilidade, à temperatura ambiente e expostas ou não à luz, durante 75 dias, verificou-se manutenção dos diâmetros médios de partículas e baixos índices de polidispersão. Entretanto, o teor de idebenona decaiu significativamente neste período, com influência significativa do tipo de polímero. Após, estudo de fotoestabilidade demonstrou que as suspensões de NC OP/PCL (UVC/UVA) e TCM/PCL (UVA) foram capazes de reduzir significativamente a degradação da idebenona (teor remanescente: 53,7-76,1%) em comparação a uma dispersão micelar aquosa contendo o fármaco (teor remanescente: 31,2-63,1%), além de promoverem liberação controlada da mesma (t1/2 26 h), sem efeito burst, com perfil ajustado ao modelo monoexponencial (t1/2<3,0 h para fármaco livre). A liofilização das suspensões, empregando trealose, um carboidrato solúvel, resultou em produtos adequados (teor entre 96-100 %; umidade inferior a 3,6 %), redispersíveis (índice de ressuspensão entre 0,8-1,2) e com a presença de inúmeras estruturas esféricas, inclusive na faixa coloidal, caracterizando a presença das NC nestes produtos secos. No estudo de estabilidade (temperatura ambiente/proteção da luz e da umidade), observou-se que os produtos liofilizados foram capazes de retardar ou diminuir significativamente a degradação da idebenona em comparação às suspensões de origem, independentemente do tipo de polímero (PCL/EUD) e de óleo (OP/OC/TCM). Sendo assim, os sistemas desenvolvidos são promissores para a liberação controlada do neuroprotetor idebenona.

Introdução: A doença hepática gordurosa não alcoólica é caracterizada pelo acúmulo hepático de lipídeos, principalmente na forma de triglicerídeos. Devido à atividade inflamatória progressiva pode evoluir para uma forma mais grave, a esteatohepatite não alcoólica. Os ácidos graxos poli-insaturados ômega-3 são associados a efeitos metabólicos positivos para redução da esteatose hepática, no entanto, são mais susceptíveis a peroxidação lipídica. Os triglicerídeos de cadeia média (TCMs) promovem a prevenção do bloqueio da beta-oxidação de ácidos graxos e redução da peroxidação lipídica, no entanto os efeitos na redução da esteatose ainda são controversos. Objetivo: O objetivo do estudo foi avaliar as implicações da dieta hiperlipídica (HL+) com óleo de peixe ou com óleo de TCM no desenvolvimento da esteatose hepática, no perfil de ácidos graxos hepáticos e no estresse oxidativo em ratos. Metodologia: Cinquenta ratos machos da linhagem wistar foram divididos em 5 grupos. Os animais receberam água e comida a vontade durante 45 dias. A adaptação a dieta HL+ foi realizada nos primeiros 15 dias. A composição da dieta do grupo que recebeu somente a gordura animal (HL+GA) era de 50% de gordura animal, e a dieta dos grupos HL+OS, HL+TCM e HL+OP era composta por 35% de gordura animal e 15% de óleo de soja, óleo de TCM e óleo de peixe, respectivamente. Resultados: Todos os grupos que receberam as dietas hiperlipídicas apresentaram maior acúmulo de gordura total e de triglicerídes hepaticos e somente os grupos HL+GA e HL+TCM apresentaram maior acúmulo de colesterol total hepático em relação ao controle. O grupo HL+TCM apresentou maior acúmulo percentual de gordura e um exacerbado acúmulo de triglicerídeos hepáticos em relação aos grupos alimentados com as dietas HL+. A redução do colesterol total sérico foi observada nos grupos HL+TCM e HL+OP, comparados ao controle. A maior incorporação hepática dos ácidos graxos EPA e DHA no grupo HL+OP contribuiu para o aumento do Índice de Peroxibilidade dos ácidos graxos e das substâncias reativas ao ácido tiobarbitúrico livres e totais e para a depleção da vitamina E no fígado. A maior razão AGS/AGPI hepática observada no grupo HL+TCM contribuiu para a preservação dos antioxidantes hepáticos. A alanina aminotransferase, um marcador de dano hepático, apresentou-se aumentada em todos os grupos que receberam as dietas HL+. Conclusões: A dieta hiperlipídica foi eficiente na indução do acúmulo de gordura hepática. O uso do óleo de TCM foi associado a uma maior concentração de lipídeos e preservação dos antioxidantes hepáticos. A dieta hiperlipídica com óleo de peixe foi associada ao aumento significativo na peroxidação lipídica, apesar do menor acúmulo de colesterol e triglicerídeos hepaticos. / Introduction: The Non-alcoholic Fatty liver disease is characterized by hepatic accumulation of lipids, mainly in the form of triglycerides. The disease may progress to a more severe form, the Non-alcoholic steatohepatitis, due to progressive inflammatory activity. Many authors have shown positive metabolic effects associated with the use of polyunsaturated omega-3 fatty acids and reduction in hepatic steatosis. However, these fatty acids are more susceptible to lipid peroxidation. The medium chain triglycerides (MCTs) are able to block beta-oxidation of fatty acids and reduce lipid peroxidation, but the MCT effects in steatosis are still controversial. Objective: The aim of this study was to assess the implications of high-fat diet (HF+) with fish oil or with MCT oil in the development of hepatic steatosis, liver fatty acid profile and oxidative stress markers in rats. Methodology: Fifty wistar male rats were divided into 5 groups. The animals had free access to food and water for 45 days. The first 15 days was dedicated for adaptation to high-fat diet. The HF+AF group received high-fat diet with 50% of animal fat and the other high-fat diets were made with 35% of animal fat plus 15% of other types of fat: soybean oil (HF+SO), MCT oil (HF+MCT) and fish oil (HF+FO). Results: The high-fat groups had higher hepatic total fat and triglycerides accumulation and only the groups HF+AF and HF+MCT had higher accumulation of hepatic cholesterol compared to control. The HF+MCT group had the highest percentage of hepatic fat accumulation and an exacerbated triglyceride accumulation in the liver among HF+ groups. The serum total cholesterol decreased in groups HF+MCT and HF+FO compared with the control group. The highest incorporation of hepatic fatty acids EPA and DHA in the HF+FO group contributed to the increased fatty acids peroxidizability index and total and free hepatic TBARS and depletion of hepatic vitamin E. The biggest ratio SFA/PUFA of liver fatty acids observed in the HF+MCT group contributed to the preservation of hepatic antioxidants. The alanine aminotransferase is a liver damage marker and was increased in all high-fat groups. Conclusions: The high-fat diet was effective to increase the hepatic fat concentration. The consumption of MCT oil can increase the hepatic lipid concentration and hepatic antioxidants. There was a significant increase in hepatic lipid peroxidation in the HF+FO group, although hepatic cholesterol and triglycerides were decreased.

La stéatose hépatique est une affection caractérisée par l'accumulation d'un excès de graisse dans le foie d'un individu sans antécédents d'abus d'alcool. La stéatose hépatique est en train de devenir la maladie chronique du foie la plus répandue dans le monde. En l'absence de thérapies approuvées, les modifications du mode de vie, y compris les interventions diététiques, restent la seule stratégie thérapeutique. Dans cette étude, nous avons cherché à déterminer si un régime riche en graisses (HFD) complété par des triglycérides à chaîne moyenne (TCM) atténue la stéatose hépatique chez les souris. Des souris mâles âgées de 7 semaines C57BL/6 ont été nourries avec un régime riche en graisses puis ont été randomisées pour rester sous régime riche en graisses ou passer à un régime riche en graisses complété par des TCM ou à un régime pauvre en graisses (LFD). Comparées aux souris nourries au HFD, les souris nourries au HFD supplémenté en TCM ont présenté une amélioration significative du degré de stéatose et d'inflammation et une amélioration des tests de tolérance au glucose et à l'insuline avec des changements modestes dans les lipides circulants et les teneurs en triacylglycérol et en cholestérol du foie. Notre étude démontre qu’une diète en gras supplémenté en TCM a des effets bénéfiques sur la stéatose hépatique. Les améliorations observées semblent être liées à la réduction de la teneur hépatique en céramides et en diacylglycérols, améliorant la sensibilité à l’insuline, et faisant des TCM une option non-pharmacologique viable à inclure dans la prise en charge de cette maladie débilitante. / Hepatic steatosis is a condition where excess fat accumulates in an individual's liver without a history of alcohol abuse. Hepatic steatosis is becoming the most common chronic liver disease worldwide. In the absence of approved therapies to specifically treat hepatic steatosis, lifestyle modifications, including dietary interventions, remain the only therapeutic strategy. In this study, we sought to determine whether a high-fat diet (HFD) supplemented with medium-chain triglycerides (MCT) attenuates hepatic steatosis in mice. Seven-week-old C57BL/6 male mice were fed HFD for 12 weeks to induce hepatic steatosis, then mice were randomized to remain on HFD or switch to either HFD supplemented with MCT or low-fat diet (LFD) for 6 weeks. Mice switched to LFD were used as another model of dietary interventions. Compared with mice fed HFD, mice fed HFD supplemented with MCT exhibited significant improvement in the degree of steatosis and inflammation as well as improvement in glucose and insulin tolerance tests with modest changes in circulating lipids and liver triacylglycerol and cholesterol contents, the hallmark of hepatic steatosis. Our study demonstrates that HFD supplement with MCT has beneficial effects on hepatic steatosis. The observed improvements seem to be linked to reductions in hepatic ceramide and diacylglycerol content, which ultimately prevents protein kinase C-ε translocation to the plasma membrane and improves insulin sensitivity, making a dietary supplement like MCTs, a viable non-pharmacological option in the management of this debilitating disease.