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

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INTRODUCTION have also been demonstrated in all tyrosine residues (Takahashi et al. 2002). Nitrated α- synuclein is more prone to aggregation (Giasson et al. 2000, Zhang et al. 2000), more resistant to proteolysis and more immunogenic explaining why inflammatory responses are frequent in PD patients (Goedert 2001, Benner et al. 2008). We have previously also commented that PINK-1 and DJ-1 are known to possess protective function against oxidative stress (Savitt et al. 2006, Thomas and Beal 2007). 44 Oxidative and nitrosative stress can also impair cellular systems that protect against misfolded or aggregated proteins. As an example, parkin can be S-nitrosylated on a critical CySH residue within its catalytic RING domains impairing its E3 ligase activity and neuroprotective functions (Chung et al. 2004, Yao et al. 2004). Additionally, DA can covalently modify parkin leading to parkin aggregation and weakening its ligase activity (LaVoie et al. 2005). S-nitrosylated and DA-modified parkin were observed in the SNpc of PD patients. Moreover, normal UPS function can also be compromised by the tendency of oxidized proteins to be more resistant to proteasomal degradation probably by means of the formation of aggregates (Friguet and Szweda 1997, Davies 2001). Protein aggregates may also lead to the UPS impairment by blocking the access of the proteasome to other proteins (Grune et al. 2004). Despite being the major site of ROS formation, the respiratory chain itself is targeted by oxidative stress. Complex I and various enzymes in the Krebs cycle can be inactived by oxidation (Cadenas and Davies 2000, Cecarini et al. 2007) contributing to the reduction of the ATP biosynthesis. Moreover, mitochondrial DNA (mtDNA) that is transitorily connected to the inner mitochondrial membrane is particularly vulnerable to oxidative damage (Goetz and Gerlach 2004). Consequently ROS-induced mtDNA injury may play a part in mitochondrial dysfunction (Stewart and Heales 2003).
Excitotoxicity INTRODUCTION Glutamate is the major excitatory neurotransmitter in the CNS, but it can be toxic to cells. Excitotoxicity is a pathological process that may occur as a consequence of an excessive stimulation of the glutamate N-methyl-D-aspartate receptor (NMDAR) and other receptors associated with glutamatergic signalling, such as metabotropic glutamate receptors (mGLURs), calcium channels and other G-protein coupled receptors (GPCR), and the subsequent massive influx of extracellular calcium. This toxic and pathological increase in cytoplasmic calcium activates a number of calcium- dependent enzymes involved in the catabolism of proteins, phospholipids and nucleic acids, and in the synthesis of NO leading in turn to mitochondrial damage, formation of oxidizing species, and downstream activation of cell death pathways. There is some evidence implicating excitotoxicity as one contributing mechanism to the pathogenesis in PD. As the SN receives rich glutamatergic inputs from neocortex and the STN, the demise of nigrostriatal DA in PD leads to disinhibition of striatal neurons, and consequently to disruption of the neurotransmitter balance in striatum resulting in glutamatergic overactivity, whereas under physiological conditions there is equilibrium between the activation of striatal neurons through NMDAR and inhibition by the D2 receptors. It was hypothesized that weak excitotoxicity may happen secondary to a mitochondrial defect with decreased ATP formation leading to an ATP dependent magnesium-blockade of the NMDAR or to disinhibition of glutamatergic STN neurons resulting from DA depletion (Beal 1998, Rodriguez et al. 1998). Furthermore, NMDAR antagonists were shown to provide protection against MPP + - induced neurotoxicity and obtain antiparkinsonian like activity in animal models (Turski et al. 1991, Uitti et al. 1996, Schmidt and Kretschmer 1997) whereas compounds that enhance NMDAR function worsens parkinsonian symptoms (Giuffra et al. 1993). In addition, NO has been associated with NMDAR excitotoxicity. During over-activation of the NDMAR, nNOS is recruited to the glutamate receptor by a postsynaptic density protein called PSD-95 and synthesizes then NO which can react with other ROS to form the highly toxic ONOO ●─ (Sattler et al. 1999, Aarts et al. 2002). 45
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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
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 and 66: DA metabolism as a source of ROS IN
Page 67: Contribution of oxidative and nitro
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
Page 116 and 117: 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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