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

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INTRODUCTION Nitric oxide 42 There is evidence that not only ROS but also the metabolism of NO, a free radical, may play a part in oxidative damage in PD (Gerlach et al. 1999, Torreilles et al. 1999, Boje 2004). NO is synthesized from L-arginine by three isoforms of nitric oxide synthase (NOS): inducible (iNOS), endothelial (eNOS), and neuronal NOS (nNOS), using NADPH and molecular oxygen (Kavya et al. 2006). NO has long been recognized as a signaling molecule for vasodilatation and neurotransmission but it has many important functions in other physiologic systems, such as in the immune, respiratory, neuromuscular and nervous systems. Moreover, NO also participates in pathogenic pathways. It can react with other ROS to generate the highly toxic RNS (Reynolds et al. 2007, Szabo et al. 2007). As depicted in Figure 19 NO can react with O2 ●─ to form the more reactive ONOO ●─ . Peroxynitrite is known to promote cellular damages by means of lipid peroxidation, DNA fragmentation, protein nitration, and activation of caspase dependent and/or independent cell death pathways (Beckman and Koppenol 1996, Hong et al. 2004, Szabo et al. 2007). Additionnally, when reacted with H + or CO2, ONOO ●─ can further convert to nitrogen dioxide (NO2) and ● OH, two highly toxic intermediates. Protein modifications by NO and/or ONOO ●─ such as S-nitrosylation and nitration may affect cell survival. Protein nitration by NO or ONOO ●─ usually inserts a nitro (-NO2) group onto one of the two carbons of the aromatic ring of tyrosine residues to form nitrotyrosine (Gow et al. 2004). On the other hand S-nitrosylation, which also happens under both physiologic and pathogenic conditions, regulates gene transcription, vesicular trafficking, receptor mediated signal transduction, and apoptosis (Chung 2007). Many enzymes, receptors and neuroprotective proteins may be modified by NO through their reactive cysteine (CySH) thiols to form the corresponding nitrosothiols (Stamler et al. 1992, Ahern et al. 2002, Hess et al. 2005, Chung 2007).
Contribution of oxidative and nitrosative stress to PD pathogenesis INTRODUCTION As we have previously seen, genes linked to familial PD are important in mitochondrial function or in the handling of misfolded proteins (Abou-Sleiman et al. 2006, Savitt et al. 2006, Sulzer 2007). Besides, oxidative and nitrosative stress had a significant effect on the normal function of familial PD-related gene products in the process of neurodegeneration. Figure 19: Generation of ROS and RNS in SNpc neuron (Tsang and Chung 2009) Oxidative stress is known to promote protein misfolding and aggregation. For example, α-synuclein can undergo oxidative modifications such as the addition of a DA adduct on α-synuclein (Conway et al. 2001). This modification stabilizes the toxic α- synuclein protofibrils and makes it resistant to chaperone mediated autophagy (CMA) leading to a complete blockade of other proteins degradation via this pathwaw (Martinez-Vicente et al. 2008). As well, α-synuclein protofibrils can permeabilize synaptic vesicles (Volles et al. 2001, Mazzulli et al. 2006, Mosharov et al. 2006) leading to an increase of more α-synuclein protofibrils. Nitrosative modifications of α-synuclein 43
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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
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 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: DA metabolism as a source of ROS IN
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
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
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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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