RESUMEN
Oxidative stress and carbonyl stress resulting from the toxicity of small aldehydes are part of the detrimental mechanisms leading to neuronal cell loss involved in the progression of neurodegenerative diseases such as Alzheimer's disease. Polyunsaturated alkylated lipophenols represent a new class of hybrid molecules that combine the health benefits of anti-inflammatory omega-3 fatty acids with the anti-carbonyl and oxidative stress (anti-COS) properties of (poly)phenols in a single pharmacological entity. To investigate the therapeutic potential of quercetin-3-docosahexaenoic acid-7-isopropyl lipophenol in neurodegenerative diseases, three synthetic pathways using chemical or chemo-enzymatic strategies were developed to access milligram or gram scale quantities of this alkyl lipophenol. The protective effect of quercetin-3-DHA-7-iPr against cytotoxic concentrations of acrolein (a carbonyl stressor) was assessed in human SHSY-5Y neuroblastoma cells to underscore its ability to alleviate harmful mechanisms associated with carbonyl stress in the context of neurodegenerative diseases.
Asunto(s)
Ácidos Grasos Omega-3 , Enfermedades Neurodegenerativas , Humanos , Quercetina/farmacología , Estrés Oxidativo , Ácidos Grasos Omega-3/farmacología , Ácidos Docosahexaenoicos/farmacología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismoRESUMEN
Polyunsaturated fatty acids (PUFAs) are a class of fatty acids that are closely associated with the development and function of the brain. The most abundant PUFA is docosahexaenoic acid (DHA, 22:6 n-3). In humans, low plasmatic concentrations of DHA have been associated with impaired cognitive function, low hippocampal volumes, and increased amyloid deposition in the brain. Several studies have reported reduced brain DHA concentrations in Alzheimer's disease (AD) patients' brains. Although a number of epidemiological studies suggest that dietary DHA consumption may protect the elderly from developing cognitive impairment or dementia including AD, several review articles report an inconclusive association between omega-3 PUFAs intake and cognitive decline. The source of these inconsistencies might be because DHA is highly oxidizable and its accessibility to the brain is limited by the blood-brain barrier. Thus, there is a pressing need for new strategies to improve DHA brain supply. In the present study, we show for the first time that the intranasal administration of nanovectorized DHA reduces Tau phosphorylation and restores cognitive functions in two complementary murine models of AD. These results pave the way for the development of a new approach to target the brain with DHA for the prevention or treatment of this devastating disease.
RESUMEN
Oil-in-water nanoemulsions are used in numerous biomedical applications as delivery systems. The droplet size in the nanometer range and their composition were extensively developed for carrying and enhancing the absorption of lipophilic drugs and lipids of interest. In the present study, critical parameters involved in the spontaneous nanoemulsification process such as the temperature, the oil type, the surfactant-to-oil and water-to-oil ratios were investigated. The aim was to design a solvent-free procedure for the spontaneous nanoemulsification at a low temperature of a large variety of triglycerides including vegetable oils. Nanoemulsification of medium-chain triglyceride (MCT) was not dependent on the temperature while nanodroplets of long-chain triglycerides (LCT) were only obtained by reaching the cloud point of ethoxylated surfactant Kolliphor® HS15. The molar volume of triglycerides was considered as a predictive parameter governing both, the spontaneous nanoemulsification at low temperature and the Ostwald ripening rate. The physical mixture of MCT and LCT was a promising strategy to prepare stable and fine nanoemulsions at 37 °C. They were characterized by a hydrodynamic diameter comprised between 20 and 30 nm and a narrow size distribution. These findings pave the way to new applications for the parenteral nutrition and the delivery of thermosensitive drugs and lipophilic molecules such as antioxidants.
Asunto(s)
Aceites de Plantas , Tensoactivos , Emulsiones , Tamaño de la Partícula , TriglicéridosRESUMEN
Vitamin E, the most important lipophilic radical scavenging antioxidant in vivo, has a pivotal role in brain. In an earlier study, we observed that adult mice with a defect in the gene encoding plasma phospholipid transfer protein (PLTP) display a moderate reduction in cerebral vitamin E levels, and exacerbated anxiety despite normal locomotion and memory functions. Here we sought to determine whether dietary vitamin E supplementation can modulate neurotransmitter levels and alleviate the increased anxiety phenotype of PLTP-deficient (PLTP -/-) mice. To address this question, a vitamin E-enriched diet was used, and two complementary approches were implemented: (i) "early supplementation": neurotransmitter levels and anxiety were assessed in 6 months old PLTP -/- mice born from vitamin E-supplemented parents; and (ii) "late supplementation": neurotransmitter levels and anxiety were assessed in 6 months old PLTP -/- mice fed a vitamin E-enriched diet from weaning. Our results show for the first time that an inadequate supply of vitamin E during development, due to moderate maternal vitamin E deficiency, is associated with reduced brain vitamin E levels at birth and irreversible alterations in brain glutamate levels. They also suggest this deficiency is associated with increased anxiety at adulthood. Thus, the present study leads to conclude on the importance of the micronutrient vitamin E during pregnancy.
RESUMEN
Oxidative stress is recognized as one of the earliest and most intense pathological processes in Alzheimer's disease (AD), and the antioxidant vitamin E has been shown to efficiently prevent amyloid plaque formation and neurodegeneration. Plasma phospholipid transfer protein (PLTP) has a major role in vitamin E transfers in vivo, and PLTP deficiency in mice is associated with reduced brain vitamin E levels. To determine the impact of PLTP on amyloid pathology in vivo, we analyzed the vulnerability of PLTP-deficient (PLTP-KO) mice to the toxic effects induced by intracerebroventricular injection of oligomeric amyloid-ß 25-35 (Aß 25-35) peptide, a non-transgenic model of AD. Under basal conditions, PLTP-KO mice showed increased cerebral oxidative stress, increased brain Aß 1-42 levels, and a lower expression of the synaptic function marker synaptophysin, as compared with wild-type mice. This PLTP-KO phenotype was associated with increased memory impairment 1 week after Aß25-35 peptide injection. Restoration of brain vitamin E levels in PLTP-KO mice through a chronic dietary supplementation prevented Aß 25-35-induced memory deficits and reduced cerebral oxidative stress and toxicity. We conclude that PLTP, through its ability to deliver vitamin E to the brain, constitutes an endogenous neuroprotective agent. Increasing PLTP activity may offer a new way to develop neuroprotective therapies.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/genética , Fragmentos de Péptidos/toxicidad , Proteínas de Transferencia de Fosfolípidos/deficiencia , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Fosfatidilcolinas/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Esfingomielinas/metabolismo , alfa-Tocoferol/metabolismoRESUMEN
Lipopolysaccharides (LPS) are components of Gram-negative bacteria. The cellular response from the host to LPS is mediated through stepwise interactions involving the lipopolysaccharide-binding protein (LBP), CD14, and MD-2, which produces the rearrangement of TLR4. In addition to LBP, the lipid transfer/lipopolysaccharide-binding protein gene family includes the phospholipid transfer protein (PLTP). Here we show that the intravascular redistribution of LPS from the plasma lipoprotein-free fraction toward circulating lipoproteins is delayed in PLTP-deficient mice. In agreement with earlier in vitro studies, which predicted the neutralization of the endotoxic properties of LPS when associated with lipoproteins, significant increases in the plasma concentration of proinflammatory cytokines were found in PLTP-deficient as compared with wild type mice. Similar inflammatory damage occurred in tissues from wild type and PLTP-deficient mice 24 h after one single intraperitoneal injection of LPS but with a more severe accumulation of red blood cells in glomeruli of LPS-injected PLTP-deficient mice. Complementary ex vivo experiments on isolated splenocytes from wild type and PLTP-deficient mice further supported the ability of cell-derived PLTP to prevent LPS-mediated inflammation and cytotoxicity when combined with lipoprotein acceptors. Finally, PLTP deficiency in mice led to a significant increase in LPS-induced mortality. It is concluded that increasing circulating levels of PLTP may constitute a new and promising strategy in preventing endotoxic shock.
Asunto(s)
Citocinas/sangre , Endotoxemia/sangre , Mediadores de Inflamación/sangre , Lipopolisacáridos/toxicidad , Proteínas de Transferencia de Fosfolípidos/sangre , Proteínas de Transferencia de Fosfolípidos/deficiencia , Proteínas de Fase Aguda/genética , Animales , Proteínas Portadoras/sangre , Proteínas Portadoras/genética , Citocinas/genética , Endotoxemia/inducido químicamente , Endotoxemia/genética , Endotoxemia/patología , Inflamación/sangre , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/patología , Receptores de Lipopolisacáridos/sangre , Receptores de Lipopolisacáridos/genética , Antígeno 96 de los Linfocitos/sangre , Antígeno 96 de los Linfocitos/genética , Glicoproteínas de Membrana/sangre , Glicoproteínas de Membrana/genética , Ratones , Ratones Noqueados , Bazo/metabolismo , Bazo/patología , Factores de TiempoRESUMEN
OBJECTIVE: Phospholipid transfer protein (PLTP) is a multifunctional, extracellular lipid transport protein that plays a major role in lipoprotein metabolism and atherosclerosis. Recent in vivo studies suggested that unlike systemic PLTP, macrophage-derived PLTP would be antiatherogenic. The present study aimed at characterizing the atheroprotective properties of macrophage-derived PLTP. METHODS AND RESULTS: Peritoneal macrophages were isolated from PLTP-deficient and wild-type mice and their biochemical characteristics were compared. It is shown that macrophages isolated from PLTP-deficient mice have increased basal cholesterol content and accumulate more cholesterol in the presence of LDL compared with wild-type cells. Cholesterol parameters in macrophages of PLTP-deficient mice were normalized by dietary alpha-tocopherol supplementation. CONCLUSIONS: The antiatherogenic properties of macrophage-derived PLTP are related at least in part to its ability to reduce cholesterol accumulation in macrophages through changes in the alpha-tocopherol content and oxidative status of the cells.
Asunto(s)
Colesterol/metabolismo , Suplementos Dietéticos , Macrófagos Peritoneales , Proteínas de Transferencia de Fosfolípidos/deficiencia , Vitaminas/farmacología , alfa-Tocoferol/farmacología , Animales , Lipoproteínas LDL/metabolismo , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Malondialdehído/metabolismo , Ratones , Ratones NoqueadosRESUMEN
Vitamin E supplementation constitutes a promising strategy in the prevention of neurodegenerative diseases. Here, we show that a phospholipid transfer protein (PLTP) is widely expressed in the brain where it appears to function as a transfer factor for alpha-tocopherol, the main isomer of vitamin E. PLTP deficiency results in significant depletion of brain alpha-tocopherol in both homozygous (-30.1%, P<0.0002) and heterozygous (-18.0%, P<0.05) PLTP knocked-out mice. Alpha-tocopherol depletion in PLTP-deficient homozygotes is associated with the elevation of lipofuscin (+25% and +450% increases in cortex and substantia nigra, respectively), cholesterol oxides (+54.5%, P<0.05), and cellular peroxides (+32.3%, P<0.01) in the brain. Complete PLTP deficiency in homozygotes is accompanied by increased anxiety as shown by fewer entries (8.3% vs. 44.4% in controls, P<0.01) and less time spent (1.7% vs. 41.3% in controls, P<0.05) in the open arms of an elevated plus-maze, in the absence of locomotor deterioration. Thus, the vitamin E transfer activity of PLTP appears to be a key process in preventing oxidative damage in the brain, and PLTP-deficient mice could be a new model of the contribution of oxidative brain injury in the etiology of neurodegenerative diseases.
Asunto(s)
Ansiedad/etiología , Proteínas de la Membrana/deficiencia , Proteínas de Transferencia de Fosfolípidos/deficiencia , Vitamina E/metabolismo , Animales , Ansiedad/fisiopatología , Trastornos de Ansiedad/etiología , Trastornos de Ansiedad/fisiopatología , Biomarcadores/metabolismo , Química Encefálica , Femenino , Ratones , Ratones Congénicos , Ratones Noqueados , Estrés Oxidativo/fisiologíaRESUMEN
Vitamin E is a lipophilic anti-oxidant that can prevent the oxidative damage of atherogenic lipoproteins. However, human trials with vitamin E have been disappointing, perhaps related to ineffective levels of vitamin E in atherogenic apoB-containing lipoproteins. Phospholipid transfer protein (PLTP) promotes vitamin E removal from atherogenic lipoproteins in vitro, and PLTP deficiency has recently been recognized as an anti-atherogenic state. To determine whether PLTP regulates lipoprotein vitamin E content in vivo, we measured alpha-tocopherol content and oxidation parameters of lipoproteins from PLTP-deficient mice in wild type, apoE-deficient, low density lipoprotein (LDL) receptor-deficient, or apoB/cholesteryl ester transfer protein transgenic backgrounds. In all four backgrounds, the vitamin E content of very low density lipoprotein (VLDL) and/or LDL was significantly increased in PLTP-deficient mice, compared with controls with normal plasma PLTP activity. Moreover, PLTP deficiency produced a dramatic delay in generation of conjugated dienes in oxidized apoB-containing lipoproteins as well as markedly lower titers of plasma IgG autoantibodies to oxidized LDL. The addition of purified PLTP to deficient plasma lowered the vitamin E content of VLDL plus LDL and normalized the generation of conjugated dienes. The data show that PLTP regulates the bioavailability of vitamin E in atherogenic lipoproteins and suggest a novel strategy for achieving more effective concentrations of anti-oxidants in lipoproteins, independent of dietary supplementation.