Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

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INTRODUCTION Aluminium influx and efflux into the brain 62 The brain has lower aluminium concentrations (about 1%) than many other tissues (Yokel and McNamara 2001), but it is an important target organ for aluminium- toxicity. Even as the BBB is highly selective to a great variety of substances, including metals, aluminium is able to cross it and enter the brain from blood (Yokel 2002b) and to accumulate in nerve and glial cells. Although the mechanism(s) responsible for aluminium transport at the BBB has not been clarified yet, it has been reported that aluminium can penetrate into the brain as a complex with transferrin by a receptor- mediated endocytosis (Roskams and Connor 1990) and also bound to citrate via a specific transporter, being the system Xc � (L-glutamate/L-CySH exchanger) the most recently accepted candidate (Nagasawa et al. 2005). There is also evidence for transporter-mediated efflux from the brain, the organic anion transporting polypeptide (oatp) family was suggested to be a candidate (Yokel 2006). The existence of a long apparent half-life of aluminium in brain tissue has been used to explain its easy accumulation into the brain following aluminium administration (Yokel et al. 2001b, Baydar et al. 2003, Sánchez-Iglesias et al. 2007b). The elimination half-life of aluminium from human brain is calculated to be seven years (Yokel and McNamara 2001). This assumption and the long life of neurons could be involved in the elevated levels of aluminium found in the brain of some patients suffering PD (Hirsh et al. 1991, Good et al. 1992, Yasui et al. 1992) and AD (Crapper et al. 1973, Perl and Brody 1980), a statement that, on the other hand, will not be understoo as the principal cause of those disorders. Since aluminium and its compounds are widely distributed in the environment (food, drinking water, airborne contaminants) and extensively used in a variety of products and processes (antiperspirants, antacids, intravenous solutions), it has aroused considerable health concern, due to both its common exposure and its particularly reported ability to cause neurodegeneration (Exley 1999, Yokel 2000, Zatta et al. 2003, Kawahara 2005). As we have previously seen, the daily reported mean dietary intake of
INTRODUCTION 3.5 mg may be increased by the frequent use of aluminium-containing antiperspirants and non-prescription drugs (Weburg and Berstad 1986, Flarend et al. 2001), as well as by occupational exposure to this metal (Meyer-Baron et al. 2007). Putative mechanisms of aluminium neurotoxicity No biological function has yet been attributed to aluminium, for which reason it is considered a nonessential metal (Yokel 2002a). However, aluminium neurotoxicity was first outlined by Dölken in 1897. Since then, aluminium accumulation in the brain has been repetitively linked to various neurodegenerative diseases (Yokel 2000, Zatta et al. 2003, Kawahara 2005). As a matter of fact, this non-redox active metal has been demonstrated to be a toxicant that is implicated in dialysis encephalopathy (Alfrey et al. 1976), osteomalacia (Parkinson et al. 1979), non-iron responsible anemia (Elliot et al. 1978), and also linked to many other diseases including AD (Exley 1999, Flaten 2001, Gupta et al. 2005), amyotrophic lateral sclerosis (Kurland 1988), and PD (Dexter et al. 1989, Yasui et al. 1992, Good et al. 1992). Aluminium was shown to be overaccumulated in the brain of post-mortem patients compared to healthy individuals (Perl et al. 1982, Yasui et al. 1992, Ward and Mason 1987) Many reviews have been published on the toxic effects of aluminium. Nevertheless, and despite all hitherto reported data concerning aluminium neurotoxicity, no single unifying mechanism responsible for its neurotoxicity has been identified. Therefore, several interlinked hypotheses have been proposed, highlighting distinct events as a basis for the beginning of aluminium toxic brain damage. 63
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Universidade de Santiago de Compost
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Don Ramón Soto Otero y Doña Estef
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Acknowledgements The work of this t
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Abbreviations AA ascorbic acid AD A
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Abbreviations (continuation) PCC pr
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List of figures (continuation) Chap
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TABLE OF CONTENTS INTRODUCTION ....
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CHAPTER 3 Brain oxidative stress an
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INTRODUCTION PARKINSON’S DISEASE
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INTRODUCTION PD is found in all eth
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Bradykinesia INTRODUCTION Bradykine
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INTRODUCTION predate the occurrence
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Table 1: Differential diagnostic in
Page 35 and 36: INTRODUCTION Table 3: National Inst
Page 37 and 38: Figure 4: Dopamine catabolism (Mén
Page 39 and 40: The basal ganglia INTRODUCTION The
Page 41 and 42: The death of SNpc DAergic neurons I
Page 43 and 44: INTRODUCTION the dorsomedial part o
Page 45 and 46: INTRODUCTION characterized as are l
Page 47 and 48: INTRODUCTION (Olanow et al. 2004).
Page 49 and 50: Etiology and pathogenesis of PD INT
Page 51 and 52: Ageing INTRODUCTION Ageing remains
Page 53 and 54: INTRODUCTION The finding of MPTP to
Page 55 and 56: INTRODUCTION may clarify why many n
Page 57 and 58: Misfolding and aggregation of prote
Page 59 and 60: INTRODUCTION (E3) (Figure 18A). Los
Page 61 and 62: INTRODUCTION in connection with Par
Page 63 and 64: INTRODUCTION Oxidative damage happe
Page 65 and 66: DA metabolism as a source of ROS IN
Page 67 and 68: Contribution of oxidative and nitro
Page 69 and 70: Excitotoxicity INTRODUCTION Glutama
Page 71 and 72: INTRODUCTION al. 1996, Cicchetti et
Page 73 and 74: Experimental models of PD INTRODUCT
Page 75 and 76: INTRODUCTION induce selective DAerg
Page 77 and 78: ALUMINIUM General features INTRODUC
Page 79 and 80: INTRODUCTION Varying amounts of alu
Page 81 and 82: INTRODUCTION and antiperspirants co
Page 83 and 84: INTRODUCTION approximately 3% of al
Page 85: Excretion INTRODUCTION As insoluble
Page 89 and 90: INTRODUCTION Oteiza 1999), non-iron
Page 91 and 92: Aluminium as a cell membrane menace
Page 93 and 94: INTRODUCTION mobilization of Ca 2+
Page 95: Aluminium impairs neurotransmission
Page 99 and 100: AIMS OF THE PRESENT THESIS The main
Page 101: OBJETIVOS
Page 104 and 105: OBJETIVOS 3) Evaluar de forma preci
Page 107: CHAPTER 1 Time-course of brain oxid
Page 110 and 111: CHAPTER 1 INTRODUCTION 86 6-OHDA (2
Page 112 and 113: CHAPTER 1 MATERIALS AND METHODS Che
Page 114 and 115: CHAPTER 1 followed by centrifugatio
Page 116 and 117: CHAPTER 1 RESULTS Effects of 6-OHDA
Page 118 and 119: CHAPTER 1 DISCUSSION 94 As shown by
Page 120 and 121: CHAPTER 1 strategies or to study th
Page 122 and 123: CHAPTER 1 Fig. 2 Changes in PCC in
Page 125: CHAPTER 2
Page 129 and 130: ABSTRACT CHAPTER 2 In the present w
Page 131 and 132: MATERIALS AND METHODS Chemicals CHA
Page 133 and 134: CHAPTER 2 atomization used were 1,5
Page 135 and 136: DISCUSSION CHAPTER 2 Aluminium ente
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Table 1. Graphite furnace programme
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CHAPTER 3 Brain oxidative stress an
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CHAPTER 3 INTRODUCTION 120 The huma
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CHAPTER 3 MATERIALS AND METHODS Che
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CHAPTER 3 1:15 for hippocampus and
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CHAPTER 3 initially incorporated to
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CHAPTER 3 RESULTS In vivo effects o
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CHAPTER 3 Effects of aluminium admi
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CHAPTER 3 DISCUSSION 132 Aluminium
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CHAPTER 3 hippocampus, showed simil
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CHAPTER 3 assume that the distinct
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CHAPTER 3 Fig. 1 Levels of TBARS (A
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CHAPTER 3 Fig. 2 Enzyme activity of
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CHAPTER 3 Fig. 3 Microphotographs s
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CHAPTER 3 Fig. 5 Levels of TBARS (A
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CHAPTER 3 Fig. 6 In vitro effects o
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SUMMARY
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SUMMARY values were attained at 48
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SUMMARY neurodegeneration in the DA
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CONCLUSIONS The results obtained in
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13) Aluminium does affect neither M
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RESUMEN RESUMEN Desde el punto de v
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RESUMEN zonas cerebrales excepto en
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CONCLUSIONES
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CONCLUSIONES Capítulo 2 4) La admi
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CONCLUSIONES 172 En base a las conc
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Publications as a direct result fro
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