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

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INTRODUCTION Neurochemical and neuropathological features of PD Dopamine 12 Dopamine (DA) plays important roles in control movement, motivation and reward, behaviour and cognition, mood, sleep, attention and learning. This biogenic monoamine is synthesized in the catecholaminergic neurons from L-tyrosine. First, tyrosine hydroxylase (tyrosine 3-monooxygenase, TH) converts L-tyrosine to 3,4- dihydroxy-L-phenylalanine (L-DOPA). TH requires 5,6,7,8-tetrahydrobiopterin (BioH4) as a coenzyme (Agid 1991). The second step is catalyzed by the DOPA decarboxylase (aromatic L-amino acid decarboxylase, AADC), L-DOPA is decarboxylated to DA (Figure 3). In some neurones, beta-hydroxylase processes DA into noradrenaline, which is metabolized to adrenaline by phenylethanolamine N-methyltransferase. DA is degraded by catechol-O-methyl transferase (COMT), aldehyde dehydrogenase (ADH) and monoamine oxidase (MAO) (Figure 4). MAO-A and -B also degrade other monoamines including serotonin, noradrenaline, and adrenaline. Figure 3: Dopamine synthesis (Méndez-Álvarez and Soto-Otero 2004) L-tyrosine tyrosine hydroxylase HO COO HO HO H 2N HN N O H N N H NH 3 O 2 CH CH CH3 OH OH 5,6,7,8-tetrahydrobiopterin (BioH 4) NAD dihydrobiopterin reductase NADH + H HN H 2O NH 3 COO 3,4-dihydroxy-L-phenylalanine (L-DOPA) HN N O H N N CH CH CH3 OH OH quinonoid dihydrobiopterin (BioH 2) CO 2 aromatic L-amino acid decarboxylase (pyridoxal phosphate) HO NH 3 HO dopamine (DA)
Figure 4: Dopamine catabolism (Méndez-Álvarez and Soto-Otero 2004) HO NH 3 HO dopamine (DA) O 2 INTRODUCTION H2O2 HO CHO H2O + NAD monoamine oxidase HO 3,4-dihydroxyphenylacetaldehyde (DOPAL) aldehyde dehydrogenase NADH + H CH 3 H 2O O HO NH 4 catechol-O-methyltransferase COO homovanillic acid (HVA) S-adenosyl-homocysteine (SAH) S CH 2 CH2 CH NH3 COO CH 2 OH O N N OH NH 2 N N HO HO COO 3,4-dihydroxyphenylacetic acid (DOPAC) CH3 S CH2 CH2 CH NH3 COO CH 2 OH O N N OH NH 2 N S-adenosyl-methionine (SAM) DA is a neurotransmitter widely distributed throughout the whole brain, but mostly localized in the striatum. It is produced by mesencephalic neurons of the substantia nigra (SN) and ventral tegmental area (VTA), and by hypothalamic neurons of the arcuate and periventricular nuclei (Cooper et al. 1996). DAergic neurons located in these areas project their axons to the striatum (nigrostriatal pathway), neocortex (mesocortical pathway), limbic system (mesolimbic pathway) and hypophysis (tuberoinfundibular pathway) (Figure 5). DA receptor family consists of five members divided into two subfamilies: the D1-like family comprises D1 and D5 receptors, whereas the D2-like family includes D2, D3 and D4 receptors (Cooper et al. 1996, Jackson and Westlind-Danielsson 1994). D1 receptors are widely expressed in the brain, whereas D2 receptors are principally seen in the striatum and nucleus accumbens (Figure 6). As we will discuss later, DA plays a central role in the pathology of PD as this neurotransmitter is crucial for basal ganglia regulation. N 13
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: INTRODUCTION Table 3: National Inst
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
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
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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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