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

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CHAPTER 1 INTRODUCTION 86 6-OHDA (2,4,5-trihydroxyphenylethylamine; 6-OHDA) is a selective catecholaminergic neurotoxin widely used to produce DAergic lesions in the nigrostriatal system (Dauer and Przedborski 2003). The main use of these lesions is to create experimental models of PD that provide insight into the molecular mechanisms involved in the development of PD in order to test new strategies for DAergic neuroprotection, and to experiment with transplantation approaches (Aebischer et al. 1991, He et al. 2001, Soto-Otero et al. 2002, Muñoz et al. 2004, López-Real et al. 2005). The structural similarity of 6-OHDA with both DA and noradrenaline makes it an appropriate ligand for the plasma membrane transporter systems of DA (DAT) and noradrenaline (Luthman et al. 1989). This feature, together with the inability shown by 6-OHDA to cross the BBB (Garver et al. 1975), makes the protocol chosen for a specific DAergic lesion in the nigrostriatal system extremely important. The main protocol used consists of the stereotaxic intracerebral injection of the toxin into a specific area of the nigrostriatal systems, which includes the stria tum, the medial forebrain bundle or the SN (Javoy et al. 1976). The intrastriatal injection of 6-OHDA is generally performed unilaterally, using the contralateral side as a control (Ungerstedt 1971). It has been shown that the intrastriatal administration of 6-OHDA causes a rapid degeneration of nigrostriatal terminals as early as 24 h, and the loss of tyrosine hydroxylase immunoreactivity (TH-ir) increases for up to 5 days following the lesion (Ichitani et al. 1991). Presumably, the neurotoxicity of 6-OHDA is attributed to its ability to generate ROS, and it is a well-known fact that under physiologyical conditions this compound is rapidly oxidized by molecular oxygen to give H2O2, � OH and the corresponding p- quinone. Although, the Fenton reaction could be involved in the formation of the hazardous � OH during the autoxidation of 6-OHDA, this is done without the involvement of the ferrous ion or any other transitionmetal ion (Marti et al. 1997). At this point, it seems interesting to highlight the reported ability of ascorbate to enhance the production of ROS by 6-OHDA (Soto-Otero et al. 2000, Méndez-Álvarez et al.
CHAPTER 1 2001), particularly due to the fact that 6-OHDA is always administered in a saline solution containing about 2% of ascorbate. In these cases, the presence of ascorbate sets a redox-cycling, which regenerates 6-OHDA from its p-quinone leading to a continuous production of ROS. Moreover, the presence of the enzyme dehydroascorbate reductase in the brain may contribute to sustaining this redox-cycling. Although, this is the molecular mechanism generally accepted to explain the ability of 6-OHDA to produce oxidative stress and consequently responsible for its neurotoxicity, it has been also reported that 6-OHDA can act directly by inhibiting the mitochondrial respiratory chain at the level of complex I (Glinka and Youdim 1995, Glinka et al. 1996, Glinka et al. 1998). Assuming the reported capacity of complex I inhibitors to increase the leakage of superoxide anions from the electron transport chain (Brand et al. 2004), this latter mechanism could also contribute to increase the ability of 6-OHDA to produce ROS and consequently to generate oxidative stress. Recent reports refer to the potential contribution of ER stress to the cell death induced by 6-OHDA (Yamamuro et al. 2006). Despite the widespread use of the intrastriatal injection of 6-OHDA to obtain an experimental model of parkinsonism and an awareness of the morphological changes following its administration (Jonsson 1983, Jeon et al. 1995), no data has been reported on the kinetics of the oxidative damage it induces in the nigrostriatal system. However, this information is crucial when this model is exploited to assess the anti-parkinsoniam properties of new drugs (Jiang et al. 1993) or the benefit of transplantation or gene therapy to repair the damaged pathways (He et al. 2001, Björklund et al. 2002). In the light of this, the aim of the present study was to investigate the time-course of the oxidative damage caused by unilateral and intrastriatal administration of 6-OHDA in the ipsilateral and contralateral side of both striatum and ventral midbrain, and also includes a quantification of the changes observed in the indices of lipid peroxidation (TBARS) and oxidative status of proteins (PCC and PTC). 87
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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
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
Page 104 and 105: OBJETIVOS 3) Evaluar de forma preci
Page 107: CHAPTER 1 Time-course of brain oxid
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
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
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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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