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

INTRODUCTION
reduced activity in the “direct” pathway and increased activity in the “indirect”
pathway, resulting in excessive GPi/SNpr inhibitory output to the thalamus (Figure 11).
These changes lead to a hypokinetic disorder characterized by inhibition of movement
(Kreitzer and Malenka 2008).
Figure 10: Human brain sections immunostained for DAT of normal person (A) and PD patient (B)
(Betarbet et al. 2002)
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Neuroimaging and pathological studies suggest that there is a long latency
between nigral degeneration begin and symptoms onset. The presymptomatic latent
phase was estimated to be approximately 6 years in idiopathic PD and longer in familial
PD (Fearnley et al. 1991, Morrish et al. 1996, Hilker et al. 2005). This long
asymptomatic period indicates that compensatory mechanisms are able to deal with
progressively lower DA levels in order to preserve apparent normal BG function. These
compensatory mechanisms which comprise increased striatal DA turnover and receptor
sensitivity, upregulation of striatopallidal enkephalin levels, increased subthalamic
excitation of GPe, and maintenance of cortical motor area activation (Bezard et al. 1999,
Bezard et al. 2001), might be potentially damaging to nigral neurons through rising
cellular metabolic demand, oxidative stress, and excitotoxicity (Rodriguez et al. 1998,
Jenner 2003).
The PD-associated cell loss has a characteristic topology distinct from the
pattern seen in the course of normal aging of the human organism as the SN is
characterized by a low level of neuronal degeneration (Kubis et al. 1995). Furthermore,
normal aging-related morphological modifications were found to be most intensive in