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

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CHAPTER 3 hippocampus, showed similar behaviour patterns and emphasize a significant decrease in the enzyme activity of most antioxidant systems, and agree with previous studies (Julka and Gill 1996a, Dua and Gill 2001, Abubakar et al. 2004a, Nehru and Anand 2005, Jyoti et al. 2007). Our in vitro experiments show no significant modification in the enzyme activity of either of SOD, GPx, and CAT, which we interpret as a declination of the gene expression of antioxidant enzymes (González-Muñoz et al. 2008).This reduction in antioxidant enzyme activity helps to explain the brain oxidative stress observed following aluminium administration. Furthermore, the reduction in GPx activity also explains the increase in the ratio GSH/GSSG previously reported by other authors (Esparza et al. 2003, Khanna and Nehru 2007), which helps explain the increase in the PTC found after aluminium exposure. The inability of aluminium to affect both MAO-A and MAO-B activity discards their involvement in the aluminium-induced brain oxidative stress. Data showing a partial disagreement with our findings have also been reported (Esparza et al. 2005), but is possibly due to the regimen of aluminium administration. A putative explanation for the increase in the activity of SOD, GPx, and CAT in the hippocampus (Sánchez-Iglesias et al. 2007b), may be the existence of a compensatory mechanism due to the ability of cells to increase the expression of antioxidant enzymes when exposed to high levels of toxicants (Gechev et al. 2002), an effect which could overcome the ability of moderate levels of aluminium to inhibit gen expression of antioxidant enzymes. Another interpretation could be the confinement of aluminium in granulovacuoles of neurofibrillar tangles due to its high capacity to interact with tau proteins in hippocampal cells (Walton 2006), thus reducing the presence of free aluminium and consequently its disposition to affect the activity of antioxidant enzymes and generate oxidative stress. Although, our findings contrast with those of Julka and Gill (1996a), similar results were also found by Esparza et al. (2003). 134 We used an animal model of PD induced by 6-OHDA administration in the third ventricle to assess the ability of aluminium to affect both the index of oxidative stress in the nigrostriatal system and the extent of lesions of the DA system in the striatum. Our results showed that aluminium causes an enhancement in 6-OHDA-induced lipid peroxidation and protein oxidation (except for PTC in ventral midbrain). The administration of aluminium alone (i.e. without 6-OHDA) also caused a significant
CHAPTER 3 difference in the levels of both lipid peroxidation and protein oxidation for PCC. Although, these results are in partial agreement with the results obtained with non- lesioned rats, they do not agree with the in vitro results obtained using brain mitochondria preparations, in which we found no significant effect due to the presence of aluminium. Evidently, these findings corroborate the importance of the in vivo studies in this kind of investigation, which appears to be a consequence of the tight relationship existing among the different molecular mechanisms coexisting within the brain. Our immunochemical study showed that aluminium administration alone caused no significant change in TH-ir striatal terminals. In contrast, lesion with 6-OHDA caused a loss of TH-ir striatal terminals, which was significantly increased with the administration of aluminium. Obviously, these data show the ability of aluminium to increase the capacity of 6-OHDA to cause nigrostriatal neurodegeneration. Evidently, the importance of these data is increased by the ability of neuromelanin to bind aluminium which may be the cause of the high concentration of aluminium found in the brain of certain patients suffering PD (Yasui et al. 1992). Furthermore, our results also help us understand the reported ability of aluminium to potentiate etiological agents and accelerate the progression of a disease (Exley and Esiri 2006). In conclusion, aluminium acts mainly as a pro-oxidant probably by reducing the activity of defence antioxidant enzymes. In addition, the increase in oxidative stress together with enhanced 6-OHDA- induced neurodegeneration, suggest the participation of free radical-induced oxidative cell injury in mediating aluminium neurotoxicity. Interestingly, we demonstrated that aluminium neither enhanced lipid peroxidation nor decreased antioxidant enzyme activities in the hippocampus. Given that aluminium content was markedly increased in the hippocampus (Sánchez-Iglesias et al. 2007b), this dual effect could be related to the biphasic behaviour of aluminium previously reported by Abubakar et al. (2004a). In our opinion, the high concentration of aluminium in the hippocampus may possibly induce an increase in defence enzyme levels, which could cause the steady state of TBARS levels after aluminium exposure. However, in the remaining cerebral areas, antioxidant enzymes have a lower activity, which is interpreted as a consequence of the postulated oxidant potential of AlO2 ●2+ (Kong et al. 1992, Exley 2004a) and consequently the factor responsible for the oxidative impairment found in those brain areas. Finally, we 135
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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
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INTRODUCTION the dorsomedial part o
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INTRODUCTION characterized as are l
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INTRODUCTION (Olanow et al. 2004).
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Etiology and pathogenesis of PD INT
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Ageing INTRODUCTION Ageing remains
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INTRODUCTION The finding of MPTP to
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INTRODUCTION may clarify why many n
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Misfolding and aggregation of prote
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INTRODUCTION (E3) (Figure 18A). Los
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INTRODUCTION in connection with Par
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INTRODUCTION Oxidative damage happe
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DA metabolism as a source of ROS IN
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Contribution of oxidative and nitro
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Excitotoxicity INTRODUCTION Glutama
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INTRODUCTION al. 1996, Cicchetti et
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Experimental models of PD INTRODUCT
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INTRODUCTION induce selective DAerg
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ALUMINIUM General features INTRODUC
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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
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
Page 144 and 145: CHAPTER 3 INTRODUCTION 120 The huma
Page 146 and 147: CHAPTER 3 MATERIALS AND METHODS Che
Page 148 and 149: CHAPTER 3 1:15 for hippocampus and
Page 150 and 151: CHAPTER 3 initially incorporated to
Page 152 and 153: CHAPTER 3 RESULTS In vivo effects o
Page 154 and 155: CHAPTER 3 Effects of aluminium admi
Page 156 and 157: CHAPTER 3 DISCUSSION 132 Aluminium
Page 160 and 161: CHAPTER 3 assume that the distinct
Page 162 and 163: CHAPTER 3 Fig. 1 Levels of TBARS (A
Page 164 and 165: CHAPTER 3 Fig. 2 Enzyme activity of
Page 166 and 167: CHAPTER 3 Fig. 3 Microphotographs s
Page 168 and 169: CHAPTER 3 Fig. 5 Levels of TBARS (A
Page 170 and 171: CHAPTER 3 Fig. 6 In vitro effects o
Page 173: SUMMARY
Page 176 and 177: SUMMARY values were attained at 48
Page 178 and 179: SUMMARY neurodegeneration in the DA
Page 181 and 182: CONCLUSIONS The results obtained in
Page 183: 13) Aluminium does affect neither M
Page 187 and 188: RESUMEN RESUMEN Desde el punto de v
Page 189 and 190: RESUMEN zonas cerebrales excepto en
Page 191: CONCLUSIONES
Page 194 and 195: CONCLUSIONES Capítulo 2 4) La admi
Page 196 and 197: CONCLUSIONES 172 En base a las conc
Page 199 and 200: Publications as a direct result fro
Page 201: REFERENCES
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