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

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CHAPTER 2 INTRODUCTION 106 Aluminium is one of the most abundant metals in the earth‟s crust and all around present in our domestic environment. Although, it is considered a non-essential element for living organisms, the medical interest in this metal comes from the reported neurotoxicity of aluminium (Yokel 2000). The bioavailabilility of aluminium, its ability to cross the BBB, and the relatively slow rate of elimination from the brain, contribute to guarantee the accumulation of aluminium into the brain (Priest 2004), which represents an enhanced neurotoxicological risk. Thus, aluminium has been implicated in aging-related changes (Deloncle et al. 2001) and several neurodegenerative diseases (Kawahara 2005). Although, it is generally accepted that the neurotoxicity of aluminium is caused by its ability to increase oxidative damage in the brain (Moumen et al. 2001), the molecular mechanisms by which it causes neuronal damage are not fully understood (Zatta et al. 2002). Evidently, the non-redox nature of this metal, so as the extensive range of values reported in the literature concerning its accumulation in the brain, contribute greatly to this uncertain situation. The purpose of this study was to elucidate the precise localization of the absorbed aluminium in the brain following the use of two different administration routes, oral and intraperitoneal, in order to clarify its distribution in the brain and in this way contribute to understand all the factors involved in its neurotoxicity.
MATERIALS AND METHODS Chemicals CHAPTER 2 Nitric acid 69% Hiperpur� from Panreac SA (Barcelona, Spain) was used to perform microwave digestions. H2O2 30% Suprapur� and a dogfish muscle DORM-2 certified reference material were purchased from Merck (Darmstadt, FRG) and from the National Research Council (Otawa, Canada), respectively. Argon N50 (99.999% purity) was used as a sheath gas for the atomizer and to purge internally. Aluminium chloride hexahydrate was purchased from Sigma Chemical Co. (St. Louis, MO, USA). The water used for the preparations of solutions was of 18.2 M� (Milli-RiOs/Q-A10 grade, Millipore Corp., Bedford, MA, USA). All remaining chemicals used were of analytical grade and were purchased from Fluka Chemie AG (Buchs, Switzerland). Animal treatment Forty male Sprague-Dawley rats (200-250 g) were used in this study. All experiments were performed in accordance with the NIH publication “Principles of laboratory animal care” and approved by the Ethics Committee of the University of Santiago de Compostela. Animals were randomly divided into four experimental group: the first group was daily i.p. injected with aluminium chloride (Sigma Chemical Co.) in saline (0.9% NaCl) at a dose of 10 mg aluminium/kg/day (pH 4) for one week. The second group was i.p. injected with saline over the same period. The third group was given orally 25 mg aluminium/kg/day and 89 mg citric acid/kg/day in saline for one week. After this period, aluminium and citric acid doses were increased to 50 mg/kg/day and 178 mg/kg/day, respectively, for one more week. Finally, doses were adjusted to 100 mg aluminium/kg/day and 356 mg citric acid/kg/day for two additional weeks. Citric acid was added to enhance the gastrointestinal absorption of aluminium (Gómez et al. 1999). The fourth group was given saline orally during the entire 107
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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
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INTRODUCTION Table 3: National Inst
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Figure 4: Dopamine catabolism (Mén
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The basal ganglia INTRODUCTION The
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The death of SNpc DAergic neurons I
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INTRODUCTION the dorsomedial part o
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INTRODUCTION characterized as are l
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INTRODUCTION (Olanow et al. 2004).
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Etiology and pathogenesis of PD INT
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Ageing INTRODUCTION Ageing remains
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INTRODUCTION The finding of MPTP to
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INTRODUCTION may clarify why many n
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Misfolding and aggregation of prote
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INTRODUCTION (E3) (Figure 18A). Los
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INTRODUCTION in connection with Par
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INTRODUCTION Oxidative damage happe
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DA metabolism as a source of ROS IN
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Contribution of oxidative and nitro
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Excitotoxicity INTRODUCTION Glutama
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INTRODUCTION al. 1996, Cicchetti et
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Experimental models of PD INTRODUCT
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INTRODUCTION induce selective DAerg
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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 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
Page 129: ABSTRACT CHAPTER 2 In the present w
Page 133 and 134: CHAPTER 2 atomization used were 1,5
Page 135 and 136: DISCUSSION CHAPTER 2 Aluminium ente
Page 137: Table 1. Graphite furnace programme
Page 141: CHAPTER 3 Brain oxidative stress an
Page 144 and 145: CHAPTER 3 INTRODUCTION 120 The huma
Page 146 and 147: CHAPTER 3 MATERIALS AND METHODS Che
Page 148 and 149: CHAPTER 3 1:15 for hippocampus and
Page 150 and 151: CHAPTER 3 initially incorporated to
Page 152 and 153: CHAPTER 3 RESULTS In vivo effects o
Page 154 and 155: CHAPTER 3 Effects of aluminium admi
Page 156 and 157: CHAPTER 3 DISCUSSION 132 Aluminium
Page 158 and 159: CHAPTER 3 hippocampus, showed simil
Page 160 and 161: CHAPTER 3 assume that the distinct
Page 162 and 163: CHAPTER 3 Fig. 1 Levels of TBARS (A
Page 164 and 165: CHAPTER 3 Fig. 2 Enzyme activity of
Page 166 and 167: CHAPTER 3 Fig. 3 Microphotographs s
Page 168 and 169: CHAPTER 3 Fig. 5 Levels of TBARS (A
Page 170 and 171: CHAPTER 3 Fig. 6 In vitro effects o
Page 173: SUMMARY
Page 176 and 177: SUMMARY values were attained at 48
Page 178 and 179: 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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