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

More documents

Recommendations

Info

INTRODUCTION Although the 6-OHDA model does not replicate many features of PD, such as extranigral pathology or LB-like inclusions (Dauer and Przedbroski 2003, Lane and Dunnett 2008), it is still extensively used. This model is particularly useful to quantitatively assay the anti-PD properties of compounds for pharmacological screening. Other 6-OHDA models, like bilateral intrastriatal (Roedter et al. 2001) or intraventricular administration of 6-OHDA (Rodriguez et al. 2001, Rodríguez-Díaz et al. 2001, Rey et al. 2007, Sánchez-Iglesias et al. 2009), were successfully developed with methods meant to cause a bilateral and more slowly arising PD. MPTP 50 MPTP is one of the most common toxins used to mimic the hallmarks of PD. Its metabolite MPP + is a potent complex I inhibitor in DAergic neurons and an excellent substrate for DAT, a fact that explains its selectivity towards DAergic neurons. Acute, subacute and chronic MPTP protocols are generally used with some variations in mice (Lau et al. 1990, Rozas et al. 1998, Petroske et al 2001, Muñoz et al. 2006, Joglar et al. 2009) as rats are not susceptible to MPTP. Loss of DAergic neurons, bradykinesia, rigidity, and posture abnormalities developed in systemic MPTP treatment (Sedelis et al. 2000). As well, small granular inclusions containing �-synuclein were seen in SN DAergic neurons, so as an extra-nigral pathology (Wallace et al. 1984, Hallman et al. 1985, Meredith et al. 2002, 2004). Recently, a technically challenging intraventricular MPP + chronic rat model has also been developed (Yazdani et al. 2006) Rotenone, paraquat and maneb Rotenone, a natural cytotoxic coumpound widely used as pesticide, is highly lipophilic and can easily cross cell membranes and the BBB. Chronic exposure of rotenone potently and uniformly inhibits mitochondrial complex I binding at the same site as MPP + throughout the rat brain. The herbicide 1,1‟-dimethyl-4,4‟-bipyridinium or paraquat (PQ) can also crosses the BBB and shares structural similarity to MPP + but has no selectivity for DAT. PQ is reduced by complex I leading to formation of a PQ radical capable of disrupting mitochondrial function. Treatments with rotenone and paraquat
INTRODUCTION induce selective DAergic neuron degeneration and have been used to model sporadic Parkinson's disease (Brooks et al. 1999, Peng et al. 2004, Hsuan et al. 2006, Inden et al. 2007). Animal models using paraquat generally also co-administer maneb (manganese ethylenebisadithiocarbamate) to enhance toxicity. Nevertheless, general toxicity of PQ and rotenone make their use difficult. As MPTP they produce nigrostriatal degeneration but their effects are more widespread. A recent study suggested that rotenone and paraquat do not induce neuroinflammation and microglial activation directly but rather indirectly as a result of DAergic neuron damage or through factors released by neurons or astrocytes (Klintworth et al. 2009). Inflammation-based models Neuroinflammation is present in PD and is believed to contribute to PD pathogenesis. Therefore, inflammation-based models have been developed. Lipopolysaccharide (LPS) is a bacterial coat protein and has been used to model neuroinflammation in PD as it is a potent activator of microglial cells and inducer of inflammation (Whitton 2007). Distinct protocols have been used by the date: acute intracerebral (Castano et al. 1998, Herrera et al. 2000, Kim et al. 2000, Iravani et al. 2005), chronic intracerebral (Gao et al. 2002), acute systemic (Quin et al. 2007), and intrauterine (Ling et al. 2002, 2004, 2006) administration of LPS. LPS causes DAergic cell death and decreases locomotor activity in rodents (Iravani et al. 2005). Gene-based models More recently, the identification of genetic mutations of PD has enabled the creation of etiologic-specific PD animal models. These include genetically modified mice with null mutations of parkin, DJ-1 and PINK1 genes (knock-out mice), an extra gene copy of �-synuclein and LRRK2, or point mutations of genes located in different PARK loci (Goldberg et al. 2003, Itier et al. 2003, Palacino et al. 2004, Von Coelln et al. 2004, Smith et al. 2006, Chesselet 2007, Dodson and Guo 2007, Kitada et al. 2007, Sang et al. 2007, Yamaguchi et al. 2007, Yang et al. 2007, Zhu et al. 2007). Additional 51
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 and 20:
TABLE OF CONTENTS INTRODUCTION ....
Page 21:
CHAPTER 3 Brain oxidative stress an
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: Experimental models of PD INTRODUCT
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 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 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
show all

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

Create successful ePaper yourself

Delete template?

Save as template?