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

CHAPTER 1
INTRODUCTION
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6-OHDA (2,4,5-trihydroxyphenylethylamine; 6-OHDA) is a selective
catecholaminergic neurotoxin widely used to produce DAergic lesions in the
nigrostriatal system (Dauer and Przedborski 2003). The main use of these lesions is to
create experimental models of PD that provide insight into the molecular mechanisms
involved in the development of PD in order to test new strategies for DAergic
neuroprotection, and to experiment with transplantation approaches (Aebischer et al.
1991, He et al. 2001, Soto-Otero et al. 2002, Muñoz et al. 2004, López-Real et al.
2005). The structural similarity of 6-OHDA with both DA and noradrenaline makes it
an appropriate ligand for the plasma membrane transporter systems of DA (DAT) and
noradrenaline (Luthman et al. 1989). This feature, together with the inability shown by
6-OHDA to cross the BBB (Garver et al. 1975), makes the protocol chosen for a
specific DAergic lesion in the nigrostriatal system extremely important. The main
protocol used consists of the stereotaxic intracerebral injection of the toxin into a
specific area of the nigrostriatal systems, which includes the stria tum, the medial
forebrain bundle or the SN (Javoy et al. 1976). The intrastriatal injection of 6-OHDA is
generally performed unilaterally, using the contralateral side as a control (Ungerstedt
1971). It has been shown that the intrastriatal administration of 6-OHDA causes a rapid
degeneration of nigrostriatal terminals as early as 24 h, and the loss of tyrosine
hydroxylase immunoreactivity (TH-ir) increases for up to 5 days following the lesion
(Ichitani et al. 1991).
Presumably, the neurotoxicity of 6-OHDA is attributed to its ability to generate
ROS, and it is a well-known fact that under physiologyical conditions this compound is
rapidly oxidized by molecular oxygen to give H2O2, � OH and the corresponding p-
quinone. Although, the Fenton reaction could be involved in the formation of the
hazardous � OH during the autoxidation of 6-OHDA, this is done without the
involvement of the ferrous ion or any other transitionmetal ion (Marti et al. 1997). At
this point, it seems interesting to highlight the reported ability of ascorbate to enhance
the production of ROS by 6-OHDA (Soto-Otero et al. 2000, Méndez-Álvarez et al.