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

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INTRODUCTION disease, especially in younger patients, but become a common complication of advanced PD. Progression of motor symptoms 6 The motor features of tremor and bradykinesia are usually localized to the upper extremities (Uitti et al. 2005). Within one to three years, they extend to the other ipsilateral limb and affect the contralateral limbs in three to eight years (Poewe and Wenning 1998). Despite the fact that PD is almost always a bilateral disease, this asymmetrical pattern remains so throughout most of the course of the illness, even in advances stages (Hughes et al. 2001). As tremor gravity is rather stable over time, whereas severity of bradykinesia and rigidity evolve similarly, some authors hypothesized the existence of different underlying pathophysiological processes (Louis et al. 1999). Non-motor symptoms Although motor features define PD, various non-motor symptoms, equally significant and potentially disabling, are typically seen. They include autonomic dysfunction (including orthostatic hypotension, bowel and bladder difficulties, abdominal bloating, constipation, urinary urgency and dysfunction, flushing, excessive sweating, temperature dysregulation, and impotence/sexual dysfunction; Jost 2003, Poewe 2008), sensory symptoms (eg. pain, paresthesiae; Quinn et al. 1986), sleep disturbances (REM sleep behaviour disorder, periodic limb movements, etc.; Stacy 2002), psychiatric changes (depression, hallucinations, anxiety symptoms), and cognitive dysfunction (memory deficits, bradyphrenia, executive function difficulty, dementia; Levin and Katzen 2005, Rippon and Marder 2005, Caviness et al. 2007). Depression is common in PD, as it develops in about 50% of individuals with PD (McDonald et al. 2003). Dementia is significantly more frequent in PD, especially in older patients, ranging from 40-80% of patients (Cedarbaum and McDowell 1987, Emre 2003, Poewe 2008). Non-motor symptoms, present with considerable variability, may
INTRODUCTION predate the occurrence of motor symptoms and should be recognized and treated as soon as possible to maximize functionality as well as quality of life. Diagnosis of PD The diagnosis of PD is essentially made on clinical criteria. Whereas these clinical criteria lead, at best, to a diagnosis of probable PD, post-mortem confirmation is required to establish a definite diagnosis of PD (Hughes et al. 1992a, Koller 1992). Historically, the identification of Lewy bodies (LB) on autopsy was considered the criterion standard for diagnosis (Gibb and Lees 1988). A diagnosis of primary parkinsonism requires at least the presence of two of the primary cardinal motor symptoms (resting tremor, bradykinesia, rigidity) and exclusion of potential causes of secondary parkinsonism. The following features are considered by most experts as essential and the most important to discriminate PD from other diagnoses: a unilateral or asymmetrical onset of motor symptoms and a consistent response of the symptoms to an adequate dose of a dopaminergic (DAergic) agent such as levodopa given for a sufficient period. If it is not the case, an alternative diagnosis should be assumed. The differential diagnosis of PD includes normal ageing, essential tremor, and other parkinsonian syndromes such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and vascular parkinsonism, amongst others (Stoessl and Rivest 1999; Table 1). The diagnosis of PD is difficult especially on early-stages of the disease, because atypical features may be absent or insignificant and there is no information on levodopa-responsiveness. A long-term follow-up of patients is needed to revise diagnoses on the basis of information on disease progression, physical examination, improvement/emergence of other symptoms and responsiveness to DAergic treatment. Post-mortem studies demonstrated misdiagnosis in up to 25% of patients diagnosed with PD by general neurologists as their brain reveal no pathological sign of the disease (Rajput et al. 1991, Hughes et al. 1992a). It is worth noting that accuracy of PD 7
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: Bradykinesia INTRODUCTION Bradykine
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 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
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INTRODUCTION and antiperspirants co
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INTRODUCTION approximately 3% of al
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Excretion INTRODUCTION As insoluble
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INTRODUCTION 3.5 mg may be increase
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INTRODUCTION Oteiza 1999), non-iron
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Aluminium as a cell membrane menace
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INTRODUCTION mobilization of Ca 2+
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Aluminium impairs neurotransmission
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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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