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

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Intranasal absorption ........................................................................................................................................................... 58 Dermal absorption ............................................................................................................................................................... 59 Distribution of aluminium in the body ................................................................................................................................. 60 Excretion .............................................................................................................................................................................. 61 Elimination rate ................................................................................................................................................................... 61 Aluminium influx and efflux into the brain ........................................................................................... 62 Putative mechanisms of aluminium neurotoxicity ................................................................................ 63 Aluminium and oxidative stress ........................................................................................................................................... 64 The brain: a target for aluminium ................................................................................................................................. 64 Aluminium catalyses iron-driven biological oxidations ................................................................................................. 65 Aluminium stimulates superoxide-/non-iron-driven biological oxidations ................................................................... 65 Aluminium-superoxide complex theory ........................................................................................................................ 66 Aluminium inhibits the antioxidant enzymes and others .............................................................................................. 66 Aluminium as a cell membrane menace .............................................................................................................................. 67 Aluminium affects cell signaling ........................................................................................................................................... 68 AIMS OF THE PRESENT THESIS ............................................................... 75 OBJETIVOS DE LA PRESENTE TESIS ......................................................... 79 CHAPTER 1 Time-course of brain oxidative damage caused by intrastriatal administration of 6-hydroxydopamine in a rat model of Parkinson’s disease ................................................................ 83 ABSTRACT ....................................................................................................................... 85 INTRODUCTION .............................................................................................................. 86 MATERIALS AND METHODS ............................................................................................ 88 Chemicals .............................................................................................................................................. 88 Animal treatment.................................................................................................................................. 88 Brain samples ........................................................................................................................................ 89 Determination of TBARS ....................................................................................................................... 89 Determination of protein carbonyl content (PCC) ................................................................................. 89 Determination of protein thiol content (PTC) ....................................................................................... 90 Statistical analysis ................................................................................................................................. 91 RESULTS .......................................................................................................................... 92 Effects of 6-OHDA administration on TBARS concentration ................................................................. 92 Effects of 6-OHDA administration on PCC ............................................................................................. 92 Effects of 6-OHDA administration on PTC ............................................................................................. 93 DISCUSSION .................................................................................................................... 94 CHAPTER 2 Analysis of brain regional distribution of aluminium in rats via oral and intraperitoneal administration ............. 103 ABSTRACT ..................................................................................................................... 105 INTRODUCTION ............................................................................................................ 106 MATERIALS AND METHODS .......................................................................................... 107 Chemicals ............................................................................................................................................ 107 Animal treatment................................................................................................................................ 107 Brain samples ...................................................................................................................................... 108 Electrothermal atomic absorption spectrometry (ETAAS) .................................................................. 108 Statistical analysis ............................................................................................................................... 109 RESULTS ........................................................................................................................ 110 Aluminium distribution in the brain after oral and i.p. administration ............................................... 110 DISCUSSION .................................................................................................................. 111
CHAPTER 3 Brain oxidative stress and selective behaviour of aluminium in specific areas of rat brain: potential effects in a 6- OHDA-induced model of Parkinson’s disease ...................................... 117 ABSTRACT ..................................................................................................................... 119 INTRODUCTION ............................................................................................................ 120 MATERIALS AND METHODS .......................................................................................... 122 Chemicals ............................................................................................................................................ 122 Animal treatment................................................................................................................................ 122 Brain samples ...................................................................................................................................... 123 Preparation of brain mitochondria ..................................................................................................... 124 Determination of TBARS, PCC, and PTC .............................................................................................. 124 Measurement of SOD activity ............................................................................................................. 125 Measurement of GPx activity .............................................................................................................. 125 Measurement of CAT activity .............................................................................................................. 126 Determination of MAO activity ........................................................................................................... 126 Immunohistochemistry ....................................................................................................................... 126 Statistical analysis ............................................................................................................................... 127 RESULTS ........................................................................................................................ 128 In vivo effects of aluminium administration on brain lipid peroxidation and protein oxidation ....................................................................................................................................... 128 In vivo effects of aluminium administration on the brain activity of different antioxidant enzymes ......................................................................................................................................... 128 Effects of aluminium administration on the degeneration of DA terminals in the striatum ......................................................................................................................................... 129 Effects of aluminium administration on brain lipid peroxidation and protein oxidation in 6-OHDA-lesioned rats and controls ............................................................................................... 130 In vitro effects of aluminium on the lipid peroxidation and protein oxidation induced by 6-OHDA autoxidation in brain mitochondrial preparations .......................................................... 131 In vitro effects of aluminium on the enzyme activities of GPx, SOD, CAT, and MAO .......................... 131 DISCUSSION .................................................................................................................. 132 SUMMARY .......................................................................................... 151 CONCLUSIONS ..................................................................................... 157 RESUMEN ............................................................................................ 163 CONCLUSIONES ................................................................................... 169 PUBLICATIONS AS A DIRECT RESULT FROM THIS THESIS ............................................. 175 PUBLICATIONS ARISING FROM COLLABORATIVE WORK DURING THIS THESIS ........... 176 REFERENCES ........................................................................................ 179
Page 1: Universidade de Santiago de Compost
Page 5: Don Ramón Soto Otero y Doña Estef
Page 9 and 10: Acknowledgements The work of this t
Page 11 and 12: Abbreviations AA ascorbic acid AD A
Page 13: Abbreviations (continuation) PCC pr
Page 16 and 17: List of figures (continuation) Chap
Page 19: TABLE OF CONTENTS INTRODUCTION ....
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 and 74:
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
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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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REFERENCES
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REFERENCES Agil A., Duran R., Barre
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REFERENCES Baquet Z. C., Bickford P
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REFERENCES 184 1,2,3,6-tetrahydropy
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REFERENCES 186 compacta of the subs
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REFERENCES Chung K. K., Dawson V. L
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REFERENCES Davies K. J. (2001) Degr
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REFERENCES Dhillon A. S., Tarbutton
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REFERENCES Ekstrand M. I., Falkenbe
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REFERENCES Fleming S. M., Delville
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REFERENCES Ghribi O., Dewitt D. A.,
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REFERENCES Good P. F., Olanow C. W.
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REFERENCES Hamilton E. I., Miniski
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REFERENCES Hirsch E. C., Brandel J.
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REFERENCES Inden M., Kitamura Y., T
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REFERENCES Johnson V. J. and Sharma
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REFERENCES Kim W. G., Mohney R. P.,
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REFERENCES Kuhn W., Winkel R., Woit
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REFERENCES 214 K.D. and Polymeropou
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REFERENCES Maraganore D. M., Lesnic
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REFERENCES McCord J. M. and Fridovi
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REFERENCES Miu A. C. and Benga O. (
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REFERENCES Nair V. D., McNaught K.,
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REFERENCES Onyango I. G. (2008) Mit
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REFERENCES Perez F. A. and Palmiter
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REFERENCES Przedborski S. and Goldm
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REFERENCES Rifat S. L., Eastwood M.
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REFERENCES Rymar V. V., Sasseville
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REFERENCES Savory J., Herman M. M.
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REFERENCES Shimizu H., Mori T., Koy
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REFERENCES 238 the generation of hy
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REFERENCES Taylor G. A., Moore P. B
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REFERENCES Um J. W., Stichel-Gunkel
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REFERENCES Vila M. and Przedborski
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REFERENCES Whitehead M. W., Farrar
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REFERENCES Yokel R. A. (2002a) Alum
Page 274:
REFERENCES Zhou W., Zhu M., Wilson
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