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

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INTRODUCTION Although the 6-OHDA model does not replicate many features of PD, such as extranigral pathology or LB-like inclusions (Dauer and Przedbroski 2003, Lane and Dunnett 2008), it is still extensively used. This model is particularly useful to quantitatively assay the anti-PD properties of compounds for pharmacological screening. Other 6-OHDA models, like bilateral intrastriatal (Roedter et al. 2001) or intraventricular administration of 6-OHDA (Rodriguez et al. 2001, Rodríguez-Díaz et al. 2001, Rey et al. 2007, Sánchez-Iglesias et al. 2009), were successfully developed with methods meant to cause a bilateral and more slowly arising PD. MPTP 50 MPTP is one of the most common toxins used to mimic the hallmarks of PD. Its metabolite MPP + is a potent complex I inhibitor in DAergic neurons and an excellent substrate for DAT, a fact that explains its selectivity towards DAergic neurons. Acute, subacute and chronic MPTP protocols are generally used with some variations in mice (Lau et al. 1990, Rozas et al. 1998, Petroske et al 2001, Muñoz et al. 2006, Joglar et al. 2009) as rats are not susceptible to MPTP. Loss of DAergic neurons, bradykinesia, rigidity, and posture abnormalities developed in systemic MPTP treatment (Sedelis et al. 2000). As well, small granular inclusions containing �-synuclein were seen in SN DAergic neurons, so as an extra-nigral pathology (Wallace et al. 1984, Hallman et al. 1985, Meredith et al. 2002, 2004). Recently, a technically challenging intraventricular MPP + chronic rat model has also been developed (Yazdani et al. 2006) Rotenone, paraquat and maneb Rotenone, a natural cytotoxic coumpound widely used as pesticide, is highly lipophilic and can easily cross cell membranes and the BBB. Chronic exposure of rotenone potently and uniformly inhibits mitochondrial complex I binding at the same site as MPP + throughout the rat brain. The herbicide 1,1‟-dimethyl-4,4‟-bipyridinium or paraquat (PQ) can also crosses the BBB and shares structural similarity to MPP + but has no selectivity for DAT. PQ is reduced by complex I leading to formation of a PQ radical capable of disrupting mitochondrial function. Treatments with rotenone and paraquat
INTRODUCTION induce selective DAergic neuron degeneration and have been used to model sporadic Parkinson's disease (Brooks et al. 1999, Peng et al. 2004, Hsuan et al. 2006, Inden et al. 2007). Animal models using paraquat generally also co-administer maneb (manganese ethylenebisadithiocarbamate) to enhance toxicity. Nevertheless, general toxicity of PQ and rotenone make their use difficult. As MPTP they produce nigrostriatal degeneration but their effects are more widespread. A recent study suggested that rotenone and paraquat do not induce neuroinflammation and microglial activation directly but rather indirectly as a result of DAergic neuron damage or through factors released by neurons or astrocytes (Klintworth et al. 2009). Inflammation-based models Neuroinflammation is present in PD and is believed to contribute to PD pathogenesis. Therefore, inflammation-based models have been developed. Lipopolysaccharide (LPS) is a bacterial coat protein and has been used to model neuroinflammation in PD as it is a potent activator of microglial cells and inducer of inflammation (Whitton 2007). Distinct protocols have been used by the date: acute intracerebral (Castano et al. 1998, Herrera et al. 2000, Kim et al. 2000, Iravani et al. 2005), chronic intracerebral (Gao et al. 2002), acute systemic (Quin et al. 2007), and intrauterine (Ling et al. 2002, 2004, 2006) administration of LPS. LPS causes DAergic cell death and decreases locomotor activity in rodents (Iravani et al. 2005). Gene-based models More recently, the identification of genetic mutations of PD has enabled the creation of etiologic-specific PD animal models. These include genetically modified mice with null mutations of parkin, DJ-1 and PINK1 genes (knock-out mice), an extra gene copy of �-synuclein and LRRK2, or point mutations of genes located in different PARK loci (Goldberg et al. 2003, Itier et al. 2003, Palacino et al. 2004, Von Coelln et al. 2004, Smith et al. 2006, Chesselet 2007, Dodson and Guo 2007, Kitada et al. 2007, Sang et al. 2007, Yamaguchi et al. 2007, Yang et al. 2007, Zhu et al. 2007). Additional 51
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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
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 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: Experimental models of PD INTRODUCT
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
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
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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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