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

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INTRODUCTION the drug users was further confirmed by the development of symptoms very similar to PD following injection of MPTP in an animal model (Burns et al. 1983). 28 Studies showed that MPTP readily crosses the blood-brain barrier (BBB) and is oxidized by MAO-B in astrocytes within glia to a pyridinium derivative, MPP + (1- methyl-4-phenyl pyridinium ion) (Ransom et al. 1987). MPP + is then selectively taken up by the DAergic cells and accumulated in nigrostriatal neurons (Chiba et al. 1985). After entering the mitochondria by the passive cationic gradient, MPP + inhibits the NADH-dehydrogenase at complex I in the respiratory chain preventing ATP synthesis and leading to reactive oxygen species (ROS) production and cell death in DAergic neurons (Chiba et al. 1984, Heikkila et al. 1985, Nicklas et al. 1985, Vyas et al. 1986, Singer and Ramsay 1990) (Figure 15). Studies showed that pre-treatment of animals with two selective MAO-B inhibitors (deprenyl or pargyline), blocked MPTP toxicity most likely by blocking MPTP oxidation to MPP + (Heikkila et al. 1984, Langston et al. 1984, Markey et al. 1984). Figure 15: MPTP metabolism (Dauer and Przedborski 2003)
INTRODUCTION The finding of MPTP toxicity not only established a link between environmental exposure and the development of PD, but also introduced MPTP as experimental model for the study of PD. Other DAergic neurotoxins have been identified, such as the insecticide rotenone and the herbicide paraquat (Brooks et al. 1999, Betarbet et al. 2000, Dhillon et al. 2008, Cannon et al. 2009). As MPTP, paraquat and rotenone are selective complex I inhibitors and induce DA diminution in animal studies. This will be discussed later in the section “Experimental models of PD”. Other environmental factors Since the discovery of MPTP-induced parkinsonism, many epidemiological studies have been performed to examine the link between the risk of PD and other environmental factors. Lifestyle-associated factors can have positive or negative influence on the risk of developing PD. Living in a rural environment (in industrialised countries), farming, exposure to pesticide use and wood preservatives, and drinking well water (Hertzman et al. 1990, Engel et al. 2001, Priyadarshi et al. 2001, Baldiet al. 2003, Gorell et al. 2004, Dick 2006) seem to confer an increased risk of PD but it remains debatable (Koller et al. 1990, Gorell et al. 1998). On the contrary, some environmental factors appear to exhibit a negative correlation with PD. Caffeine intake, cigarette smoking, and high vitamin intake are inversely associated with the risk of developing this disease (Baron 1986, Morens et al. 1995, Ross et al. 2000, Hernan et al. 2002, Lai et al. 2002, Landrigan et al. 2005, de Lau and Breteler 2006). Metals Exposure to some specific metals such as aluminium, amalgam, copper, iron, lead, manganese, mercury, zinc, and a combination of metals have also been hypothesised to be a risk factor in PD through the accumulation of metals in the SN and increased oxidative stress (Ngim and Devathasan 1989, Zayed et al. 1990, Seidler et al. 1996, Gorell et al. 1997, Gorell et al. 1999, Rybicki et al. 1999, Kuhn et al. 1998, Lai et al. 2002). During the past few years, special attention was paid to aluminium. As it will 29
Page 1: Universidade de Santiago de Compost
Page 5: Don Ramón Soto Otero y Doña Estef
Page 9 and 10: Acknowledgements The work of this t
Page 11 and 12: Abbreviations AA ascorbic acid AD A
Page 13: Abbreviations (continuation) PCC pr
Page 16 and 17: List of figures (continuation) Chap
Page 19 and 20: TABLE OF CONTENTS INTRODUCTION ....
Page 21: 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: Ageing INTRODUCTION Ageing remains
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 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
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OBJETIVOS 3) Evaluar de forma preci
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CHAPTER 1 Time-course of brain oxid
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CHAPTER 1 INTRODUCTION 86 6-OHDA (2
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CHAPTER 1 MATERIALS AND METHODS Che
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CHAPTER 1 followed by centrifugatio
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CHAPTER 1 RESULTS Effects of 6-OHDA
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CHAPTER 1 DISCUSSION 94 As shown by
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CHAPTER 1 strategies or to study th
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CHAPTER 1 Fig. 2 Changes in PCC in
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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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