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Envejecimiento poblacional y discapacidad cognitiva: función renal en síndrome de Down y aproximación terapéutica del agua sulfurada en enfermedad de Alzheimer

AutorGuzmán, Rodrigo
DirectorCasado Moragón, Ángela
Palabras claveAgente terapéutico
Tejido sanguíneo
Estrés oxidativo
Disfunción tiroidea
Fecha de publicación2013
EditorCSIC - Centro de Investigaciones Biológicas (CIB)
Universidad Complutense de Madrid
ResumenPopulation aging is a phenomenon that is happening worldwide. Thanks to advances in medicine, research and disease prevention policies, life expectancy has been increased in recent decades (Otero et al., 2004). In addition, this event has also been assisted by a decline in the fertility rate (United Nations, 2002). The main result is that groups of older population have increased their number in relation to the younger population, and predictions for the coming years indicate that this trend will continue (Kinsella et al., 2005). Spain is one of the countries with higher levels of life expectancy in the world, and predictions for the future indicate that it will be the oldest country in the whole world at year 2050 (Otero et al., 2004). In order to understand these predictions it is important to remark the important changes that Spanish society has undergone during last century, such as economic growing, massive urbanization of rural areas and general access to potable water, creation of the National Health Service, or main advances in diagnosis and treatment of different diseases (Otero et al., 2004). Thus, it has been observed that populations that formerly had a shorter life expectancy, as in the case of people with Down syndrome (DS), have attained the age in which new issues may arise related to aging organism (Bittles and Glasson, 2004; Barnhart and Connolly, 2007). On the other hand, it has been also reported an increase in the number of cases of people developing Alzheimer's disease (AD), as more and more people arriving at high ages. DS is the first cause of mental retardation in the world with a frequency of 1 out 700-1000 live births (Hook, 1981; Sherman et al., 2007). Clinical symptoms were first described by John Langdon Down in 1866, but the association with one extra copy of chromosome 21 was first reported by Lejeune (1959). DS patients present different morphological characteristics such as short stature, obesity and bilateral epicanthic eyefolds. Moreover, they have increased risk of different systemic disorders, such as thyroid dysfunction (Korsager et al., 1978). Furthermore, growth retardation has been noted during life and also they have an elevated oxidative stress that leads to premature aging and that may lead to premature onset of AD (Bush and Beail, 2004; Casado et al., 2007). In fact, between 10% and 55% of DS people from 40 to 59 years will develop EA (van Dyke et al., 1998). However, there is little evidence in scientific literature of renal function disorders.
AD is the most common cause of dementia in older people in the world. The principal clinical symptoms of the disease are general cognitive decline, loss of memory and inability to reasoning (Alzheimer, 1907). Physiological manifestations in the brain are mainly two: β-amyloid plaques and neurofibrillary tangles (Schaeffer et al., 2011). But the pathogenesis of the disease is still not clear. There are some theories about that, like the amyloid cascade hypothesis, but it has been revised several times and it remains unclear (Pimplikar, 2009). Nevertheless, it is well known that oxidative stress is one of the main cause or consequence of the disease (Aluise et al., 2010; Singh et al., 2010). Furthermore, this elevated oxidative stress can be observed notonly in brain tissue but also in peripheral tissues, such as blood tissue (Mórocz et al., 2002; Kadioglu et al., 2004; Leutner et al., 2005; Casado et al., 2008; Sultana et al., 2011). Actually, blood tissue is one of the best options to use in researching AD, since it can provide a lot of information about different issues, such as therapeutic approaches. Sulphurous water (SW) has been used as therapeutic agent since second half of twentieth century (Mozota-Sagardia, 1960; Passa, 1964; Ricci and Zaccone, 1975; Pisaneschi, 1979; Prévost et al., 1983). One of the main features of SW is the presence of hydrogen sulfide, which confers its antioxidant activity. Since oxidative stress plays an important role in AD, it was proposed as a possible treatment to improve life quality in AD patients. RESEARCH CONTENTS This Doctoral Thesis has adressed an analysis of the possible consequences of population aging in two population samples with cognitive disabilities (DS and AD). As a first objective, it has been proposed to determine if there is any failure in renal function in persons with DS, using two different renal biomarkers, creatinine (Cr) and specific gravity (SG) in urine samples. Cr was determined by a spectrophotometric method based on Jaffé reaction (Jaffé, 1986) and SG was measured using refractometry. It has been also analyzed the relationships of these biomarkers with respect to sociodemographic parameters (genre, age and diet) as well as to incidence of hypothyroidism, the most common thyroid disorder in DS (Tüysüz and Beker, 2001; Barnhart and Connolly, 2007). In the case of AD, several oxidative stress biomarkers were determined in blood tissue (damage to DNA, proteins, carbohydrates and plasmaAfterwards, a therapeutic in vitro approach of SW was performed in peripheral mononuclear cells (PMNC) using Comet assay (that measures oxidative DNA damage) and MTT assay (an indicator of cell viability). Furthermore, SW effects were compared with those produced by recognized antioxidant (vitamins C and E, and N-acetyl cysteine). Each population sample was compared with a control population from the same geographical region. DS results showed that Cr and SG were significantly decreased in SD compared to control population. Attending to genre comparisons, there were no differences between males and females in both parameters. Influence of age analysis revealed that differences in Cr and SG could be observed from adulthood. Moreover, a negative significant correlation was observed between SG and age in both populations, being the slope of linear regression two-fold higher in DS population.
Diet analysis did not indicate significant differences between populations in all kind of analyzed food intake, including meat intake. These data suggest a possible renal failure in DS maybe caused by the high oxidative stress characteristic of this syndrome. Furthermore, hypothyroidism comparison results indicated that people with DS who were medicated with levothyroxine had significant decreased levels than those without hypothyroidism, indicating that hypothyroidism may also be influencing an impaired renal function. In addition, when DS population with hypothyroidism was subtracted there were still significant differences between DS and control population, strengthening the renal failure hypothesis. Thus, new clinical and medical monitoring may have been considered in this population. AD results indicated, as it was expected, that all oxidative stress biomarkers were significantly increased compared to control population. Besides, antioxidant status biomarkers were significantly decrease compared to control population. Finally, no differences were found when influence of genre or age was studied. SW therapeutic approach results showed that SW protected in vitro against increased oxidative stress in PMNC in both populations. A decrease in parameters of oxidative damage to DNA also avoided loss of cell viability of these cells. The effect of SW in both oxidative DNA damage and cell viability parameters was similar to those of the other antioxidants used (vitamins C and E, N-acetyl cysteine), indicating that further research can be addressed to include SW as a possible therapy for AD. antioxidant capacity) to assess the oxidative status of the selected population sample. CONCLUSIONS People with DS have decreased levels of Cr and SG, primarily from adulthood. This aspect can be a symptom of its typical premature aging caused by oxidative stress. There is no influence of genre or diet, but hypothyroidism seems to be an important issue in renal function, since levothyroxine does not fix levels of Cr and SG to its normal state. Thus, a new aspect of DS population is proposed to be monitored, because life expectancy in this syndrome is increasing every decade. On the other hand, this is the first time that antioxidant effects of SW have been proved in oxidative DNA damage biomarkers related to cell viability in AD. Thus, this Doctoral Thesis opens a new way of research in therapeutics for AD to improve their quality of life. Despite further research is needed, this results supports the idea of using health resorts to treat not only AD but also other diseases related to oxidative stress, such as DS.
Descripción169 p.-34 fig.-16 tab.-2 anexox.
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