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

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SUMMARY values were attained at 48 hours post-injection for both TBARS and PCC, and at 24 hours for PTC. Interestingly, lower but significant increases in oxidative stress levels were also seen in the contralateral side (ventral midbrain and striatum) excluding this zone as a control to determine neurochemical alterations caused by 6-OHDA in this experimental model of PD. At last and according to the obtained results, we decided to establish the optimal time of 48 hours post-injection for quantification of brain oxidative stress indices when assessing the oxidative potential of aluminium in this experimental model of PD. 152 The second part of this thesis consisted in developing a dosage regimen of aluminium to rats which would guarantee a significant accumulation of this metal in brain areas and also to determine its precise distribution in the brain. As it was previously suggested that aluminium distribution depends on the animal species in question and the chemical form of aluminium administered, we opted for two distinct administration routes: oral and intraperitoneal. Sprague-Dawley rats were either daily i.p. injected with aluminium chloride (10 mg Al 3+ /kg/day) for 1 week, or given orally progressive increasing doses of aluminium chloride (25, 50, 100 mg Al 3+ /kg/day) supplemented with citrate (89, 178, 356 mg/kg/day) during 4 weeks. Our results showed that both administration routes led to aluminium accumulation. A greater and more significant increase was noted in the group receiving aluminium via intraperitoneal administration for most brain areas except in ventral midbrain. Distribution also varied with the administration route used. In accordance to these results we resolved to use the intraperitoneal administration route to clarify the brain oxidative stress provoked by aluminium. Finally the third phase of this thesis was dedicated to determine the ability of aluminium to alter the oxidant status of specific brain areas, such as cerebellum, ventral midbrain, cortex, hippocampus, and striatum. Male Sprague-Dawley rats were intraperitoneally administered with aluminium chloride (10 mg Al 3+ /kg/day) in saline for 10 days. As we demonstrated before, this dosage procedure was sufficient to insure aluminium accumulation in brain areas. Animals were sacrificed 48 hours after lesion to perform lipid peroxidation and protein oxidation studies because the peak for oxidative
SUMMARY stress is reached at this time as we previously reported in the first phase of this thesis. Our results showed that, except for hippocampus, the metal triggered an increase in oxidative stress levels (determined as TBARS, PCC, and PTC) for most of the brain regions studied, which was accompanied by decreased activities of the antioxidant enzymes (SOD, CAT, and GPx). However, studies in vitro confirmed the inability of aluminium to affect the activity of those enzymes and also of MAO-A and MAO-B. The reported effects exhibited a regional-selective behaviour for all the cerebral structures studied. Worthy of note is the case of the hippocampus, as aluminium exposure resulted in increased antioxidant enzymes activities, no significant alterations of lipid peroxidation and decreased protein oxidations. These results might be explained by the high aluminium accumulation and the promotion of compensatory mechanism(s) in this brain area. Lastly, and to shed some light on the potential of aluminium to act as an etiological factor in PD, we studied the ability of this metal to increase the striatal DAergic neurodegeneration and various indices of oxidative stress in ventral midbrain and striatum of rats injected intraventricularly with 6-OHDA. This animal model was known to induce a more slowly ensuing parkinsonian syndrome exhibiting similar topographic depletion of DAergic neurons to that observed in PD (Rodriguez et al. 2001, Rodríguez-Díaz et al. 2001) and to avoid the focal lesion around the cannula tip produced when 6-OHDA is directly injected in the brain tissues. We followed the same dosage procedure as previously mentioned (daily intraperitoneal injection of 10 mg mg Al 3+ /kg/day in saline for ten days) except that rats were lesioned on the 8 th day with 6- OHDA injected in the third ventricle. Animals were killed 1 week post-lesion for immunohistochemistry studies as it was reported that progressive degeneration of mesencephalic DAergic cells produced by intraventricular injection of 6-OHDA reached the definitive lesion pattern at the end of the first week postinjection (Rodriguez et al. 2001). Our results indicated that aluminium enhanced the ability of 6-OHDA to cause lipid peroxidation and protein oxidation (except for PTC in ventral midbrain). In addition, the metal was able to increase the capacity of 6-OHDA to cause 153
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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
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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
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 158 and 159: CHAPTER 3 hippocampus, showed simil
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 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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