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

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INTRODUCTION 70 The signal transduction pathway of mitogen-activated protein kinase (MAPK) plays also an important role in the apoptosis in neurons or astrocytes. Aluminium was demonstrated to activate in cultured cortical neurons one of the important members in MAPK family, the stress-activated protein kinase c-jun N-terminal kinase (SAPK/JNK) (Fu et al. 2003), whose phosphorylation and dephosphorylation are considered as the molecular key in stress signal transduction. SAPK/KNK activates its downstream transcription factor c-jun, which is the important component of AP-1. This latter modulates the expression of target genes and participates in the regulation of cell differentiation and apoptosis. Neuronal accumulation of aluminium affects mitochondria integrity and functionality (reviewed by Kumar and Gill 2009). The metal enters into the neuron upon cell depolarization and inhibits Na + /Ca 2+ exchange thus inducing an extreme accumulation of mitochondrial Ca 2+ . This triggers the opening of the mitochondrial transition pore (MTP) and the consequent release of cytochrome c leading finally to activation of the caspase family proteases. Studies that used intracisternal injection of the aluminium-maltolate complex have shown that aluminium targets mitochondria. Aluminium-maltolate is a lipophilic complex stable at physiological pH and proposed to be formed in the gastrointestinal tract. This neurotoxic complex produces cytoskeletal alterations (Klatzo et al. 1965, Savory et al. 1996, 1998) leading to tangle formation and cell apoptosis (Johnson et al. 2005). Aluminium-maltolate induces cytochrome c translocation, increased expression of the proapoptotic protein Bax, and decreased expression of the antiapoptotic protein Bcl-2, finally leading to cell apoptosis (Ghribi et al. 2001a, 2002). In addition, aluminium also affects the endoplasmic reticulum (ER), the major storage location for calcium, which also contains members of the Bcl-2 family, such as Bcl-2 and Bcl-XL. The stress induced by aluminium-maltolate activates caspase 12 leading to a specific type of ER-mediated cell death by apoptosis (Ghribi et al. 2001b, 2001c, 2002).
Aluminium impairs neurotransmission INTRODUCTION Aluminium has a negative impact on the main steps of the neurotransmission event which takes place at the synapse, such as synthesis and storage of neurotransmitters, triggered release from the presynaptic terminal, interaction with receptors on the postsynaptic cell, and inactivation of neurotransmitters (Gonçalves and Silva 2007). The metal may alter the physical properties of synaptic membranes which could influence the release and/or uptake of neurotransmitters, or directly inhibit the enzymes in charge of the synthesis, utilization and degradation of these molecules. There are evidences demonstrating that this metal disturbs some crucial events of DA neurotransmission. The DA metabolism appears to be altered in animal models of aluminium: DA levels are reduced by 40% in the striatum (Ravi et al. 2000) and the concentration of DA metabolites such as dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) are lower in the hypothalamus of treated animals (Tsunoda and Sharma 1999). Besides, the ability of aluminium to affect the expression of DA receptors D1 and D2 (Kim et al. 2007) and to inhibit DA-β-hydroxylase, the enzyme in charge of converting DA into noradrenaline (Milanese et al. 2001), has also been documented. Aluminium interferes also with glutamatergic, cholinergic, and GABAergic metabolisms. Actually, aluminium exposure in rats leads to decreased acetylcholine synthesis and degradation, reduction of muscarinic acetylcholine receptors (Julka et al. 1995), increased contents of glutamine and glutamate, and decreased GABA level (El-Rahman 2003, Nayak and Chatterjee 2003). Alterations of calcium metabolism may also be of importance for aluminium neurotoxicity as calcium has a crucial role in neurotransmitter release. As an example, aluminium inhibits GABA synaptosomal release and uptake as a consequence of the inhibition of Ca 2+ /CaM- dependent calcineurin activity (Cordeiro et al. 2003). 71
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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
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
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: INTRODUCTION mobilization of Ca 2+
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
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
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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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