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

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CHAPTER 1 DISCUSSION 94 As shown by the data here reported, the intrastriatal injection of 6-OHDA causes a continuous increase in the indices of oxidative stress in the ipsilateral side (striatum and ventral midbrain), which expands over 48 h for both lipid peroxidation and PCC, and over 24 h for PTC. This quick evolution of the indices of oxidative stress agrees with both morphological observations showing that DAergic neurons start to die within the first 24 h (Jonsson 1983, Ichitani et al. 1991, Jeon et al. 1995) and that rapid autoxidation of 6-OHDA takes place under physiological conditions (Soto-Otero et al. 2000, Méndez-Álvarez et al. 2001, Méndez-Álvarez et al. 2002). Once peak-values are reached, each of the indices begins a slow decline to values very close to those found in controls after 7-day post-injection. Taking into account the fact that the degeneration of the nigrostriatal system can last for 1–2 weeks (Sauer and Oertel 1994, Przedborski et al. 1995), our data appears to show that the here reported oxidative damage is the cause of the DAergic lesion and not a consequence of this process, but this is still open to question (Andersen 2004). Furthermore, the fact that the neurodegenerative process continues when the indices of oxidative stress returned to the initial values (control values) appears to prove that the oxidative stress generated by 6-OHDA autoxidation causes irreversible damage in DAergic neurons and endangers their survival. Similar findings of early oxidative stress have been observed after MPTP application (Przedborski et al. 2004) as well as after chronic treatment of rats with rotenone (Giasson et al. 2000). However, the fact that in our study the indices of oxidative stress increase simultaneously in both striatum and ventral midbrain seems to discard previous suggestions involving a chemical axotomic action of 6-OHDA in the delay and gradual degeneration of DAergic neurons found in this model of DAergic neurodegeneration (Sauer and Oertel 1994). At this point, it is interesting to note that the maximum increase in the indices of oxidative stress is higher in the ventral midbrain than in the striatum and occurs simultaneously. Assuming the accepted involvement of oxidative stress in apoptosis (Giasson et al. 2000), the apoptotic-like features observed 1–3 weeks after lesion (Marti et al. 1997), and the ability shown by caspase inhibitors to protect
CHAPTER 1 against degeneration (Trojanowski and Lee 2003), our results corroborate the involvement of the oxidative stress caused by 6-OHDA autoxidation as a triggering factor in the development of neurodegeneration. In view of both the recently reported ability of oxidative stress to act as a primary event for α-synuclein polimerization and the involvement of these aggregates in neurodegenerative processes (Cutillas et al. 1999, Krantic et al. 2005), the fibrillization of α-synuclein could also be responsible for the slow rate of neurodegeneration observed after unilateral, intrastriatal administration of 6-OHDA. Evidently, both our results and the suggested hypothesis do not discard the suggested involvement of microglia in the corresponding neuronal death (Rodrigues et al. 2001, Przedborski and Goldman 2004), because the formation of certain uncharged ROS during the 6-OHDA autoxidation, with a relatively non short half-life, makes these substances highly diffusible through biological membranes and suitable for cellular signaling (Vroegop et al. 1995, Kamsler and Segal 2004). It is also important to emphasize that the unilateral injection of 6-OHDA also caused a significant increase in the indices of oxidative stress of the contralateral side, affecting both the striatum and the ventral midbrain. Our results show that the magnitude of these increases was lower than that found in the ipsilateral side, which agree with the reported inability of intrastriatal and unilateral injections of 6-OHDA to cause loss of cell bodies in the contralateral side (Lee et al. 1996). However, these data clearly preclude the use of the contralateral side as a control to assess neurochemical changes induced by 6-OHDA in this experimental model of PD. This may be explained by the above-mentioned ability of certain ROS generated by 6-OHDA autoxidation to diffuse through biological membranes. In summary, our data confirm that intrastriatal and unilateral injections of 6- OHDA cause oxidative stress (lipid peroxidation and protein oxidation), which increases during the first 2-day post-injection and returns to approximate control levels at the 17-day post-injection. This appears to be the triggering factor for the neurodegenerative process, and the retrograde neurodegeneration following the first week post-injection seems to be a consequence of the cell damage caused within the first days post-injection. Finally, when this model is used to assess new neuroprotective 95
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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
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 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 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 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
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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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