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

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INTRODUCTION kinase 1 (PINK1) (Valente et al. 2004), and DJ-1 (Bonifati et al. 2003). New and crucial insights into the PD pathogenesis have been supplied by the discovery of these genetic mutations and the improved comprehension of dysfunction of their abnormally encoded proteins. Table 4: Gene loci associated with PD ( * Toulouse and Sullivan 2008, # Schapira 2008) Locus (MIM#) PARK1 (168601) PARK2 (600116) PARK3 (602404) PARK4 (605543) 26 Inheritance Chromosomal location Gene AD 4q21 SNCA (mutations) Onset Clinical features Mid-late Idiopathic PD, low incidence of tremor, fast progression AR 6q25.2–q27 Parkin Early Drug induced dyskinesia, dystonia, slow progression AD 2p13 Not known Late Idiopathic PD, dementia, fast progression AD 4q21 SNCA (duplication / triplication) Late Dementia, autonomic dysfunction, postural tremor, fast progression Neuropathology a Nigral degeneration, with LB Nigral degeneration, without LB Nigral degeneration, with LB, NFT and plaques Nigral degeneration, with LB, vacuoles in neurons PARK5 AD * 4p14 UCHL1 Mid-late Idiopathic PD * Not reported (191342) # 4p15 # Yes PARK6 AR * 1p36 PINK1 Early Slow progression, Not reported (605909) # 1p35 drug-induced dyskinesia PARK7 AR 1p36 DJ1 Early Slow progression, Not reported (606324) psychiatric symptoms PARK8 AD * 12q12 LRRK2 Late Idiopathic PD Nigral degeneration, (607060) # 12p12 variable features including LB, NFT and ubiquitinated inclusions PARK9 b AR * 1p36 ATP13A2 Juvenile Spasticity, Striatal atrophy (606693) # 1p32 supranuclear gaze paralysis, dementia PARK10 AD * 1p Not known Late Not reported Not reported (606852) # 1p32 PARK11 (607688) AD 2q36–q37 Not known Late Not reported Not reported PARK12 X-linked Xq21–q25 Not known Not Not reported Not reported (300557) reported PARK13 (610297) AD 2p12 Htra2 Late Idiopathic PD Not reported (601828) 2q22–q23 NR4a2 Late Idiopathic PD Not reported (603779) 5q23.1–q23.3 Synphilin1 Late Idiopathic PD Not reported a LB: Lewy bodies, NFT: neurofibrillary tangles, plaques: amyloid plaques. b PARK9 initially presented as idiopathic PD but is now known as Kufor–Rakeb syndrome.
Ageing INTRODUCTION Ageing remains an important risk factor of PD. It is associated with a decline of pigmented neurons in the SNpc (McGeer et al. 1977) and a decline in striatal DA transporters (Van Dyck et al. 2002) but no difference between the caudate and putamen as seen in PD. Even if the incidence of PD is known to increase with age, this disease is not a simple acceleration of ageing as the pattern of neuronal loss in SN in PD patients and in the normal aging population differs substantially (Kish et al. 1992). Role of environmental exposure Exposure to environmental factors may strongly influence risk of PD. Environmental factors have also been implicated in the pathogenesis of PD with varying degrees of association. These include environmental toxins, occupation, dietary factors, drug use and metals amongst others. An example of environmental toxin: MPTP The environmental toxin hypothesis considers that PD-related neurodegeneration is a consequence from exposure to a DAergic neurotoxin. MPTP (1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine) is a prototypic example of how an exogenous toxin can mimic the clinical and pathological features of PD. Davis et al. (1979) and Langston et al. (1983) were the first to convincingly demonstrate the link between environmental toxin exposure and the development of PD. They observed that, after illicit drug consumption, a series of patients developed physical symptoms consistent with PD, and acute levodopa-responsive parkinsonism. In one case, substantial damage to nigral neurones was observed (Davis et al. 1979). Analysis of the drug used revealed a contamination with two side products, MPTP and MPPP (1-methyl-4-phenyl-4- propionoxy-piperidine) in the synthesis of a meperidine analogue (Langston and Ballard 1983). The causative link between MPTP and the parkinsonian syndrome observed in 27
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: Etiology and pathogenesis of PD INT
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 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
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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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REFERENCES
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