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

DA metabolism as a source of ROS
INTRODUCTION
The selective neurodegeneration of SNpc DAergic in PD seems to suggest that
these neurons are more vulnerable to oxidative stress, but the reason behind this is not
completely understood. One potential explaination was based, at least in part, on DA
metabolism either by autoxidation or catalyzed by MAO. Actually, this neurotransmitter
can react with molecular oxygen generating peroxides, active quinones, � OH and other
ROS that, along with those created from the respiratory chain failure, may lead to both
modifications of proteins and depletion of GSH generating a highly oxidative
intracellular environment.
The MAO catalyzed oxidation of DA to 3,4-dihydroxyphenylacetaldehyde
(DOPAL) leads to H2O2 formation, which is normally cleared by GSH. As GSH levels
are decreased in SN of PD patients (Sian et al. 1994) H2O2 may be converted into � OH
which may trigger lipid peroxidation causing the death of DAergic neurons.
Furthermore, DA autoxidation results in the formation of the semiquinone radical which
can be directly toxic (Stokes et al. 1999, Danielson and Andersen 2008) or which can
lead to the formation of ROS (Olanow 1990). O2 ●─ is either metabolized into H2O2 or
reacts with NO, generating the strongly reactive ONOO ●─ . After a complex process of
polymerization, this autoxidation pathway leads finally to the generation of the dark-
coloured, insoluble pigment called neuromelanin (Graham 1978). This compound was
implicated in the vulnerability and susceptibility of DAergic neurons to
neurodegeneration (Abou-Sleiman et al. 2006) but its precise mechanism remains
uncertain. Several hypotheses tried to explain its contribution to the DAergic neurons
death, through a macromolecule crowding effect or as an intraneuronal toxic reservoir
by binding transition metals like iron or neurotoxic coumpounds like MPP + (Chung et
al. 2001).
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