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

INTRODUCTION
Nitric oxide
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There is evidence that not only ROS but also the metabolism of NO, a free
radical, may play a part in oxidative damage in PD (Gerlach et al. 1999, Torreilles et al.
1999, Boje 2004). NO is synthesized from L-arginine by three isoforms of nitric oxide
synthase (NOS): inducible (iNOS), endothelial (eNOS), and neuronal NOS (nNOS),
using NADPH and molecular oxygen (Kavya et al. 2006). NO has long been recognized
as a signaling molecule for vasodilatation and neurotransmission but it has many
important functions in other physiologic systems, such as in the immune, respiratory,
neuromuscular and nervous systems. Moreover, NO also participates in pathogenic
pathways. It can react with other ROS to generate the highly toxic RNS (Reynolds et al.
2007, Szabo et al. 2007). As depicted in Figure 19 NO can react with O2 ●─ to form the
more reactive ONOO ●─ . Peroxynitrite is known to promote cellular damages by means
of lipid peroxidation, DNA fragmentation, protein nitration, and activation of caspase
dependent and/or independent cell death pathways (Beckman and Koppenol 1996, Hong
et al. 2004, Szabo et al. 2007). Additionnally, when reacted with H + or CO2, ONOO ●─
can further convert to nitrogen dioxide (NO2) and ● OH, two highly toxic intermediates.
Protein modifications by NO and/or ONOO ●─ such as S-nitrosylation and nitration may
affect cell survival. Protein nitration by NO or ONOO ●─ usually inserts a nitro (-NO2)
group onto one of the two carbons of the aromatic ring of tyrosine residues to form
nitrotyrosine (Gow et al. 2004). On the other hand S-nitrosylation, which also happens
under both physiologic and pathogenic conditions, regulates gene transcription,
vesicular trafficking, receptor mediated signal transduction, and apoptosis (Chung
2007). Many enzymes, receptors and neuroprotective proteins may be modified by NO
through their reactive cysteine (CySH) thiols to form the corresponding nitrosothiols
(Stamler et al. 1992, Ahern et al. 2002, Hess et al. 2005, Chung 2007).