O consumo moderado de vinho tinto melhora o déficit cognitivo induzido pela hipercolesterolemia em camundongos

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Neurociências, Florianópolis, 2016.Evidências clínicas e epidemiológicas apontam a hipercolesterolemia, particularmente a hipercolesterolemia familiar, como um fator de risco para o desenvolvimento de comprometimento cognitivo leve, um estágio de transição entre o envelhecimento saudável e os primeiros sintomas da doença de Alzheimer. A hipercolesterolemia familiar é uma doença genética do metabolismo das lipoproteínas, caracterizada por níveis muito elevados de colesterol plasmático que levam à aterosclerose prematura, em consequência do prejuízo da função do receptor de lipoproteína de baixa densidade (LDL). Nesse contexto, nosso grupo de pesquisa demonstrou que camundongos nocautes para o receptor de LDL (LDLr-/-), modelo de hipercolesterolemia familiar, exibem prejuízos de memória e aprendizado, associados à disfunção colinérgica e ao estresse oxidativo no córtex préfrontal e hipocampo. Desde a atribuição do Paradoxo Francês, os polifenóis presentes no vinho tinto têm sido indicados como agentes protetores de doenças cardiovasculares. Além disso, estudos recentes demonstram o papel protetor dessas moléculas antioxidantes em doenças neurodegenerativas, com particular ênfase na doença de Alzheimer. Dessa forma, hipotetizamos que o consumo regular moderado de vinho tinto é capaz de mitigar o desenvolvimento de comprometimento cognitivo e alterações neuroquímicas nos camundongos LDLr-/-. Assim, avaliamos por testes comportamentais o efeito do consumo moderado de vinho tinto na locomoção, atividade motora e nos parâmetros cognitivos de aprendizado e memória dos animais LDLr-/- submetidos à dieta padrão ou dieta hipercolesterolêmica. Além disso, determinamos a atividade da enzima acetilcolinesterase (AChE) e parâmetros antioxidantes nos tecidos cerebrais desses camundongos. Primeiramente, nós certificamos que a concentração alcoólica de 6% é segura para o consumo dos camundongos C57BL/6. Em seguida, nós observamos que a dieta hipercolesterolêmica causa um aumento nos níveis de colesterol total plasmáticos e dano hepático nos camundongos LDLr-/-, o que não foi atenuado pelo consumo de vinho tinto. Os prejuízos de memória de curto e longo prazo observados nos camundongos LDLr-/- tratados com dieta padrão e rica em colesterol foram revertidos pelo consumo de vinho. No entanto, os efeitos benéficos da bebida foram mais efetivos quando estes camundongos são expostos a uma dieta padrão. A atividade da AChE não foi modificada pela dieta hipercolesterolêmica ou pelo consumo moderado de vinho tinto. Além disso, não foram observadas alterações no sistema antioxidante vinculado à glutationa e nos níveis de peroxidação lipídica nas estruturas cerebrais estudadas após os tratamentos. Nosso conjunto de dados demonstrou que o consumo diário e moderado de vinho tinto é capaz de melhorar o prejuízo cognitivo induzido pela hipercolesterolemia em camundongos, todavia, os mecanismos de ação pelos quais essa bebida possa estar atuando ainda não estão bem elucidados.Abstract : Clinical and epidemiological evidence have been reported that hypercholesterolemia, particularly familial hypercholesterolemia, as a risk factor for the development of mild cognitive impairment, a transitional stage between healthy aging and the earlier Alzheimer's disease. Familial hypercholesterolemia is a lipoprotein metabolism genetic disorder, characterized by high plasma cholesterol levels leading to premature atherosclerosis as a result of the loss of the low density lipoprotein (LDL) receptor function. In this regard, our research group has demonstrated that LDL receptor knockout (LDLr-/-) mice, a useful animal model of familial hypercholesterolemia, exhibit learning and memory impairments, which is associated with cholinergic dysfunction and antioxidant imbalance in prefrontal cortex and hippocampus. Since French Paradox attribution, red wine polyphenols and flavonoids are indicated as cardiovascular diseases protectors. In addition, it has been shown the protective effect of these antioxidant molecules in neurodegenerative diseases, with particular emphasis in Alzheimer s disease. In this way, we hypothesized that the regular red wine moderate consumption is be able to mitigate the development of cognitive impairments and neurochemical alterations in LDLr-/- mice. Thus, we evaluated using behavioral tests the effect of red wine moderate consumption in locomotion, motor activity and learning and memory cognitive parameters of LDLr-/- animals submitted to standard or hypercholesterolemic diet. Additionally, we determined the activity of the acetylcholinesterase (AChE) enzyme, as well as antioxidant and oxidative stress parameters in the brain tissue of these mice. Firstly, we noticed that the 6% alcohol concentration is safe for C57BL/6 mice consumption. After that, we found that hypercholesterolemic diet causes an increase in the total plasma cholesterol levels and liver damage in LDLr-/- mice, which were not prevented by the consumption of red wine. The short and long term memory loss observed in LDLr-/- mice treated with standard and high cholesterol diet were ameliorated by wine consumption. Notable, beneficial effects of the beverage were most effective when these mice were exposed to a standard diet. The AChE activity was not modified by hypercholesterolemic diet or red wine moderate consumption. In addition, no changes were observed in the glutathione system and levels of lipid peroxidation in both brain structures studied after treatments. Our data set shows that red wine daily and moderate consumption can improve the hypercholesterolemia cognitive impairment induced in mice, however, the mechanisms by which this drink may be acting are still unclear. Clinical and epidemiological evidence have been reported that hypercholesterolemia, particularly familial hypercholesterolemia, as a risk factor for the development of mild cognitive impairment, a transitional stage between healthy aging and the earlier Alzheimer's disease. Familial hypercholesterolemia is a lipoprotein metabolism genetic disorder, characterized by high plasma cholesterol levels leading to premature atherosclerosis as a result of the loss of the low density lipoprotein (LDL) receptor function. In this regard, our research group has demonstrated that LDL receptor knockout (LDLr-/-) mice, a useful animal model of familial hypercholesterolemia, exhibit learning and memory impairments, which is associated with cholinergic dysfunction and antioxidant imbalance in prefrontal cortex and hippocampus. Since French Paradox attribution, red wine polyphenols and flavonoids are indicated as cardiovascular diseases protectors. In addition, it has been shown the protective effect of these antioxidant molecules in neurodegenerative diseases, with particular emphasis in Alzheimer s disease. In this way, we hypothesized that the regular red wine moderate consumption is be able to mitigate the development of cognitive impairments and neurochemical alterations in LDLr-/- mice. Thus, we evaluated using behavioral tests the effect of red wine moderate consumption in locomotion, motor activity and learning and memory cognitive parameters of LDLr-/- animals submitted to standard or hypercholesterolemic diet. Additionally, we determined the activity of the acetylcholinesterase (AChE) enzyme, as well as antioxidant and oxidative stress parameters in the brain tissue of these mice. Firstly, we noticed that the 6% alcohol concentration is safe for C57BL/6 mice consumption. After that, we found that hypercholesterolemic diet causes an increase in the total plasma cholesterol levels and liver damage in LDLr-/- mice, which were not prevented by the consumption of red wine. The short and long term memory loss observed in LDLr-/- mice treated with standard and high cholesterol diet were ameliorated by wine consumption. Notable, beneficial effects of the beverage were most effective when these mice were exposed to a standard diet. The AChE activity was not modified by hypercholesterolemic diet or red wine moderate consumption. In addition, no changes were observed in the glutathione system and levels of lipid peroxidation in both brain structures studied after treatments. Our data set shows that red wine daily and moderate consumption can improve the hypercholesterolemia cognitive impairment induced in mice, however, the mechanisms by which this drink may be acting are still unclear