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

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CHAPTER 3 DISCUSSION 132 Aluminium is a non-redox metal whose accumulation in the brain has been linked to various neurodegenerative diseases (Yokel 2000, Zatta et al. 2003). Several hypotheses have been given to explain its reported ability to promote biological oxidations (Exley 2004a). Thus, it has been shown to facilitate iron-induced lipid peroxidation (Gutteridge et al. 1985); non-iron-induced lipid peroxidation (Verstraeten and Oteiza 2000); non-iron-mediated oxidation of NADH (Kong et al. 1992); and non- iron-mediated formation of � OH (Méndez-Álvarez et al. 2002). Additionally, it also appears to inhibit several antioxidant enzymes in different parts of the brain (Nehru and Anand 2005). In the present study aluminium was administered at a dosage regimen to guarantee its accumulation in different areas of rat brain (Sánchez-Iglesias et al. 2007b). Aluminium-treated animals remained healthy and showed no signs of toxicity during the treatment. However, certain tiny, white inclusions were observed floating in the abdominal cavity, probably caused by a partial precipitation of the aluminium and previously reported (Abubakar et al. 2004a). Previous studies have shown results ranging from no significant changes in TBARS levels (Oteiza et al. 1993b), to an increase in TBARS levels (Sharma and Mishra 2006), and a significant decrease in TBARS levels (Abubakar et al. 2004b). Our data clearly demonstrate that aluminium exposure caused a significant increase in the levels of TBARS in most of the brain areas studied, but particularly so in the cerebellum. Although, some authors have reported a decrease (Esparza et al. 2003) or no changes (Deloncle et al. 1999) in the levels of TBARS, our results are in total (Esparza et al. 2005, Nehru and Anand 2005, Dua and Gill 2001, Jyoti et al. 2007) or partial agreement (Julka and Gill 1996a) with most previously published data. Curiously, we found no significant changes in the levels of TBARS in the hippocampus following aluminium administration. In our opinion, the apparent contradictory results found in the literature are due to the use of different chemical forms for aluminium exposure (Esparza et al. 2003, Julka and Gill 1996a) and/or to the use of different
CHAPTER 3 administration routes (Deloncle et al. 1999, Jyoti and Sharma 2006) as we have demonstrated recently (Sánchez-Iglesias et al. 2007b). Another index to assess oxidative stress is the oxidant status of proteins. We found that the effects caused by aluminium on both PCC and PTC were not homogenous for all areas studied. Indeed, our data showed that aluminium provoked an increase in both PCC and PTC in the cerebellum, ventral midbrain, and striatum, whereas a decrease was found in the cortex and hippocampus. The most noteworthy effect of these results is the lack of correlation between the increase observed in the PCC, ostensibly a consequence of a situation of oxidative stress, and the apparently contradictory increase in PTC. The increase in the PTC may be a consequence of increased GSH production (Khanna and Nehru 2007) and its subsequent capacity to reduce disulfide groups in proteins. Our results contrast with previous findings that aluminium exposure affects neither PCC (Oteiza et al. 1993b) nor PTC (Oteiza et al. 1993b) in whole brain. Others report a significant increase of PCC in both hippocampus (Jyoti and Sharma 2006) and cortex (Jyoti et al. 2007) and a significant loss of PTC in whole brain (Dua and Gill 2001). Once again, this variability in relation to previous data appears to corroborate the importance of the chemical speciation of aluminium and the route of administration. Interestingly, the aluminium salt used not only affects the accumulation of this metal in different cells but also modulates its toxic effects (Lévesque et al. 2000). Despite these findings and taking into account the complexity of the aluminium speciation chemistry (Bharathi et al. 2008), it is very difficult to gain insight into the relation between the particular chemical speciation of aluminium in the brain and its biological effects. Nevertheless, our results clearly show that aluminium can create a situation of oxidative stress in most brain areas. This is mainly a consequence of the fact that aluminium is a strong Lewis acid which allows it to react with the superoxide anion and form a metal-superoxide complex (AlO2 ●2+ ), which is a more potent oxidant than the superoxide anion and putatively has a high catalytic potential, as suggested by Kong et al. (1992) and later discussed by Exley (2004a). These changes were accompanied by significant variations in the activity of SOD, GPx, and CAT. Our results indicate that all the neural tissues examined, except 133
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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 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 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
Page 204 and 205: REFERENCES Agil A., Duran R., Barre
Page 206 and 207:
REFERENCES Baquet Z. C., Bickford P
Page 208 and 209:
REFERENCES 184 1,2,3,6-tetrahydropy
Page 210 and 211:
REFERENCES 186 compacta of the subs
Page 212 and 213:
REFERENCES Chung K. K., Dawson V. L
Page 214 and 215:
REFERENCES Davies K. J. (2001) Degr
Page 216 and 217:
REFERENCES Dhillon A. S., Tarbutton
Page 218 and 219:
REFERENCES Ekstrand M. I., Falkenbe
Page 220 and 221:
REFERENCES Fleming S. M., Delville
Page 222 and 223:
REFERENCES Ghribi O., Dewitt D. A.,
Page 224 and 225:
REFERENCES Good P. F., Olanow C. W.
Page 226 and 227:
REFERENCES Hamilton E. I., Miniski
Page 228 and 229:
REFERENCES Hirsch E. C., Brandel J.
Page 230 and 231:
REFERENCES Inden M., Kitamura Y., T
Page 232 and 233:
REFERENCES Johnson V. J. and Sharma
Page 234 and 235:
REFERENCES Kim W. G., Mohney R. P.,
Page 236 and 237:
REFERENCES Kuhn W., Winkel R., Woit
Page 238 and 239:
REFERENCES 214 K.D. and Polymeropou
Page 240 and 241:
REFERENCES Maraganore D. M., Lesnic
Page 242 and 243:
REFERENCES McCord J. M. and Fridovi
Page 244 and 245:
REFERENCES Miu A. C. and Benga O. (
Page 246 and 247:
REFERENCES Nair V. D., McNaught K.,
Page 248 and 249:
REFERENCES Onyango I. G. (2008) Mit
Page 250 and 251:
REFERENCES Perez F. A. and Palmiter
Page 252 and 253:
REFERENCES Przedborski S. and Goldm
Page 254 and 255:
REFERENCES Rifat S. L., Eastwood M.
Page 256 and 257:
REFERENCES Rymar V. V., Sasseville
Page 258 and 259:
REFERENCES Savory J., Herman M. M.
Page 260 and 261:
REFERENCES Shimizu H., Mori T., Koy
Page 262 and 263:
REFERENCES 238 the generation of hy
Page 264 and 265:
REFERENCES Taylor G. A., Moore P. B
Page 266 and 267:
REFERENCES Um J. W., Stichel-Gunkel
Page 268 and 269:
REFERENCES Vila M. and Przedborski
Page 270 and 271:
REFERENCES Whitehead M. W., Farrar
Page 272 and 273:
REFERENCES Yokel R. A. (2002a) Alum
Page 274:
REFERENCES Zhou W., Zhu M., Wilson
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