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

TABLE OF CONTENTS
INTRODUCTION ....................................................................................... 1
PARKINSON’S DISEASE ...................................................................................................... 1
An overview ............................................................................................................................................ 1
Prevalence and incidence of PD .............................................................................................................. 2
Clinical characteristics of PD ................................................................................................................... 3
Resting tremor ....................................................................................................................................................................... 4
Rigidity ................................................................................................................................................................................... 4
Bradykinesia ........................................................................................................................................................................... 5
Postural instability ................................................................................................................................................................. 5
Progression of motor symptoms ............................................................................................................................................ 6
Non-motor symptoms ............................................................................................................................................................ 6
Diagnosis of PD ....................................................................................................................................... 7
Neurochemical and neuropathological features of PD ......................................................................... 12
Dopamine ............................................................................................................................................................................ 12
The basal ganglia .................................................................................................................................................................. 15
Degeneration of all DAergic pathways and other systems ................................................................................................... 20
Lewy bodies, Lewy neurites and pale bodies ....................................................................................................................... 21
The six-stage system: a novel neuropathological concept of neurodegeneration ............................................................... 23
Etiology and pathogenesis of PD .......................................................................................................... 25
Genetics of PD ...................................................................................................................................................................... 25
Ageing .................................................................................................................................................................................. 27
Role of environmental exposure .......................................................................................................................................... 27
An example of environmental toxin: MPTP................................................................................................................... 27
Other environmental factors ........................................................................................................................................ 29
Metals ........................................................................................................................................................................... 29
Potential theories ................................................................................................................................................................ 30
The “dual-hit” hypothesis ............................................................................................................................................. 30
The “multiple hit or multihit” hypothesis ...................................................................................................................... 30
The connection between PD and the FeBAD hypothesis .............................................................................................. 31
Parkinson diseases: a syndrome of different disorders ................................................................................................. 32
Misfolding and aggregation of proteins ............................................................................................................................... 33
Oxidative stress .................................................................................................................................................................... 38
Transition metals: the example of iron ......................................................................................................................... 40
DA metabolism as a source of ROS ............................................................................................................................... 41
Nitric oxide .................................................................................................................................................................... 42
Contribution of oxidative and nitrosative stress to PD pathogenesis ............................................................................ 43
Excitotoxicity ........................................................................................................................................................................ 45
Cell death pathways ............................................................................................................................................................. 48
Experimental models of PD ................................................................................................................... 49
Toxin-induced models .......................................................................................................................................................... 49
6-OHDA ......................................................................................................................................................................... 49
MPTP ............................................................................................................................................................................. 50
Rotenone, paraquat and maneb ................................................................................................................................... 50
Inflammation-based models ................................................................................................................................................ 51
Gene-based models ............................................................................................................................................................. 51
ALUMINIUM .................................................................................................................... 53
General features ................................................................................................................................... 53
Aluminium speciation .......................................................................................................................................................... 53
Sources of aluminium exposure ............................................................................................................ 54
Environmental exposure ...................................................................................................................................................... 54
Dietary exposure .................................................................................................................................................................. 55
Iatrogenic exposure ............................................................................................................................................................. 56
Occupational exposure ........................................................................................................................................................ 56
Aluminium toxicokinetics ...................................................................................................................... 57
Absorption of aluminium ..................................................................................................................................................... 57
Oral absorption .................................................................................................................................................................... 57