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

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INTRODUCTION mouse models, such as Pitx3-aphakia mouse or Engrailed double knock-out mouse, were developed on the basis of genes crucial for development and survival of DAergic neurons (Nunes et al. 2003, Sgado et al. 2006, Ding et al. 2007). Recently, tissue- specific knock-out mouse models targeting the expression of genes of interest in a region- or neuron-specific manner were created (Gelman et al. 2003, Ekstrand et al. 2004, Lindeberg et al. 2004, Backet et al. 2005, Zhuang et al. 2005, Backman et al. 2006, Borgkvist et al. 2006, Turiault et al. 2007). 52 As there is no experimental PD model to date that mimics exactly the pathogenesis and progression happening in PD, one priority at this time is to develop an experimental model of PD that reproduces the clinical and pathological features of PD, such as progressive loss of DAergic neurons in the striatum and SN, LB-like inclusion in the brain, and L-DOPA-responsive movement disorder.
ALUMINIUM General features INTRODUCTION The human organism is constantly and inevitably exposed to aluminium, a ubiquitous metal which is the third most abundant element in the Earth‟s crust (after oxygen and silicon), representing 8.3% of total components (Becaria et al. 2002). Its atomic number is 13 and its electronic configuration is [Ne]3s 2 3p 1 . Aluminium has two isotopes, Al 27 which has a natural abundance of 99.9% and Al 26 with a half-life (t1/2) of 7.2 � 10 5 years. In nature, aluminium does not occur in the elemental state but is found in combination with oxygen, fluorine, silicon, sulphur and other species (Brusewitz 1984, Wagner 1999). The physical, chemical and biological properties of the aluminium complexes will determine the toxicokinetics of this metal (Harris et al. 1997). Aluminium speciation Aluminium forms a wide range of hydroxyl complexes in water solution, evolving from Al 3+ towards [Al(OH)4] - within the 3-8 pH range (Reaction 8; Figure 21). Reaction 8: [Al(H2O)6] 3+ � [Al(H2O)5(OH)] 2+ � [Al(H2O)4(OH)2] + � Al(OH)3 � [Al(OH)4] - Actually, in aqueous solution at pH < 5.0, the prevalent mononuclear Al species is the octahedral hexahydrate [Al(H2O)6] 3+ (generally abbreviated as Al 3+ ). In less acidic solutions with pH values greater than 5.0, [Al(H2O)6] 3+ undergoes hydrolysis that yield different species such as [Al(H2O)5(OH)] 2+ (abbreviated as [Al(OH)] 2+ ) and [Al(H2O)4(OH)2] + (abbreviated as [Al(OH)2] + ). But not only mononuclear aluminium species exist in aqueous solution, as it is inclined to polymerize forming the unstable dimer [Al2(OH)2(H2O)8] 4+ and the more stable polymers [Al6(OH)12] 6+ , [Al10(OH)22] 8+ 53
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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
Page 25 and 26: INTRODUCTION PARKINSON’S DISEASE
Page 27 and 28: INTRODUCTION PD is found in all eth
Page 29 and 30: Bradykinesia INTRODUCTION Bradykine
Page 31 and 32: INTRODUCTION predate the occurrence
Page 33 and 34: 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: INTRODUCTION induce selective DAerg
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 and 86: Excretion INTRODUCTION As insoluble
Page 87 and 88: INTRODUCTION 3.5 mg may be increase
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
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ABSTRACT CHAPTER 2 In the present w
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MATERIALS AND METHODS Chemicals CHA
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CHAPTER 2 atomization used were 1,5
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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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REFERENCES
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