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

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INTRODUCTION 46 Another pathway has been linked to excitotoxicity. In PD there is evidence for abnormal activation of cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase which needs activating partners, p35 and p39 (Cheung et al. 2004, Cheung 2006). Over- activation of NMDAR was shown to provoke cleavage of p35 to p25, a protein that cause a more robust and prolonged activation of Cdk5. Excessive Cdk5 activity has been linked to PD pathogenesis (O‟Hare et al. 2005, Smith et al. 2006, Wang et al. 2007, Qu et al. 2007) and is known to contribute to neuronal death by phosphorylating the transcription factor myocyte enhancer factor 2 (MEF2) and the antioxidative stress enzyme peroxiredoxin 2 (Prx2), leading to attenuation of their normal prosurvival functions. Actually, Prx2 breaks down H2O2 to H2O and O2 protecting the cells against oxidative stress (Abou-Sleiman et al. 2006), whereas MEF2 is an important transcription factor of prosurvival genes (Potthoff and Olson 2007). Neuroinflammation and glial cells It is well known that the brain can initiate injury responses, such as neuroinflammation, as a way to clean up injured brain tissues. The main cellular responders are microglia, specialized macrophages capable of producing cytokines and other protective factors to regulate the injury response. Although neuroinflammation may have initial protective effects, it has been hypothesized to be a potential contributor to PD pathogenesis (Hartmann et al. 2003). Its exact role is unclear: it may act as an initial event of PD pathogenesis or be a downstream result of another triggering pathogenic factor. Immunohistochemical studies have demonstrated the presence of activated microglia, increased expression of iNOS, cytokines like tumour necrosis factor-α (TNF- α) and interleukin (IL)-1β, and pro-inflammatory signalling cascades such as cyclooxygenase-2 (COX-2) and NF-κB in striatum, SN and cerebrospinal fluid (CSF) of PD patients (Boka et al. 1994, Mogi et al. 1994, Blum-Degen et al. 1995, Hunot et al. 1996, Hirsh et al. 1998, Muller et al. 1998, Hunot et al. 1999, Knott et al. 2000, Nagatsu et al. 2000, Nagatsu 2002). Animal models of PD using rotenone, MPTP, and 6-OHDA showed levels of microglial activation similar to what is found in PD (Czlonkowska et
INTRODUCTION al. 1996, Cicchetti et al. 2002, Sherer et al. 2003). In post-mortem examination of brains from humans exposed to MPTP, activated microglia was present up to 16 years after exposure indicating a long-lasting and ongoing inflammatory response (Langston et al. 1999). Indeed, the inflammatory cytokines seem to intensify and perpetuate the neuroinflammation (McGeer et al. 2001, Orr et al. 2002, McGeer and McGeer 2004, Bartels and Leenders 2007). Furthermore, neuromelanin, which is released by dying DAergic neurons, was shown to activate microglia in vitro (Wilms et al. 2003). As large amounts of superoxide radicals are produced by activated microglia, chronic neuroinflammation may then promote the degeneration of DAergic neurons once activated, probably through increased oxidative stress (Figure 20; Whitton 2007). This may lead to the creation of a vicious cycle that further increases DAergic toxicity in the SNpc. Figure 20: Interaction between microglia and DAergic neurons (Whitton 2007) 47
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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
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: Excitotoxicity INTRODUCTION Glutama
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 118 and 119: 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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