ReviewNeuroprotective properties of nitric oxide and S-nitrosoglutathione
Introduction
Nitric oxide (NO) radicals generated by nitric oxide synthase (NOS) are unique endogenous molecules modulating vital physiological functions such as vasodilation and platelet aggregation (Moncada et al., 1991, Murad, 2003). The physiological actions of NO are mediated primarily through interaction of NO with heme moiety of guanylyl cyclase leading to generation of a key secondary message cGMP. In addition, generation of NO leads to formation S-nitrosothiols through multiple pathways (Do et al., 1996, Foster and Stamler, 2004, Hogg, 1999, Jaffrey et al., 2001, Kluge et al., 1997, Stamler, 1994, Wink et al., 1994). S-Nitrosothiols, such as S-nitrosglutahione (GSNO) may function as stabilizer, reserve, and carrier of NO. Growing evidence suggest that S-nitrosylation of critical thiol groups of proteins leads to S-nitrosylation-based signal transduction and modulation of protein–protein interactions along numerous pathways (Askew et al., 1995, Chiueh and Rauhala, 1999, Foster and Stamler, 2004, Jaffrey et al., 2001, Matsumoto et al., 2003, Stamler, 1994, Stamler et al., 2001). Furthermore, metabolite of GSNO, S-nitrosocysteinyl glycine may function as neuronal modulator that may regulate hypoxia-induced lung ventilation (Lipton et al., 2001).
In addition to various physiological functions, NO and NO-derived species have been reported to play double-edged roles in either neurotoxicity or neuroprotection (Chiueh and Rauhala, 1999, Chiueh, 1999, Chung et al., 2004, Gross and Wolin, 1995, Wink and Mitchell, 1998). NO as nitrogen centered radical reacts easily with various molecules such as oxygen, superoxide, thiyl, lipid peroxyl, and other free radicals leading to either antioxidant or pro-oxidant effects depending on levels of these reactive species generated (Chiueh and Rauhala, 1999, Wink and Mitchell, 1998). Simplified scheme of reaction pathways of NO and NO derived species is shown in Fig. 1. Formation of reactive nitrogen species such as peroxynitrite and reaction products of NO and oxygen have been shown to cause cyto- and neurotoxicity through both proapoptotic and necrotic mechanisms (Beckman et al., 1990, Gross and Wolin, 1995, Keynes and Garthwaite, 2004). Peroxynitrite is formed when the rate of production of superoxide anion and NO radicals are equivalent (Radi et al., 1991). However, low physiological levels of superoxide anion (Tyler, 1975) compared to NO and high levels of superoxide dismutase enzyme may limit peroxynitrite formation in vivo (Wink and Mitchell, 1998). Increasing evidence suggest that S-nitrosothiols and NO may have a normal physiological function, which may lead to protection against oxidative stress (Rauhala et al., 1998), prevention of caspase-dependent apoptosis, mediation of preconditioning-induced adaptive neuroprotection (Andoh et al., 2000, Andoh et al., 2002a, Andoh et al., 2003), and induction of neurogenesis (Zhang et al., 2001, Zhu et al., 2003) in the brain. The present review discusses these new findings underlying molecular mechanisms by which NO and S-nitrosothiols may mediate unique neuroprotective action.
Section snippets
NO and GSNO as neuroprotective antioxidants
NO is a nitrogen-centered radical, making it less reactive than oxygen-centered radicals such as hydroxyl radical, superoxide anion, and lipid peroxyl radicals. The reactivity of NO with these oxygen-centered radicals and iron (or metallo-oxo species) may contribute to its inhibition of iron-induced hydroxyl radical generation (Kanner et al., 1991) and lipid peroxidation (Rauhala et al., 1996a, Rubbo et al., 1994) in both in vitro and in vivo preparations. It is important to note that GSNO
Cyclic GMP-dependent protective effects of NO
NO is readily reacted with heme moiety of guanylate cyclase and therefore low nanomolar concentrations of NO could mediate important biological functions (Moncada et al., 1991, Murad, 2003). By using human neurotrophic SH-SY5Y cell line, it has been recently demonstrated that preconditioning-induced NOS and elevated levels of NO lead to up-regulation of antiapoptotic Bcl-2 protein and down-regulation of adaptor protein p66sch (Andoh et al., 2000). These changes were blocked by NOS and guanylyl
Antiapoptosis and cytoprotection by NO and GSNO
S-Nitrosylation of regulatory thiol group of cysteine has been suggested to be a redox-based signaling mechanism affecting protein functions (Stamler et al., 2001). It is important to note that a large range of S-nitrosylated proteins/thiols have been detected in brain (Do et al., 1996, Jaffrey et al., 2001), even the functional significance of all these modifications is not well understood. It is good to note that NO and GSNO have two distinct actions which may affect nitrosylation responses.
Possible role of NO in neuroregeneration
New neurons are observed in adult hippocampal dentate gyrus and proliferation of these neuronal stem cells is increased by stroke (Kaplan and Hinds, 1977, Zhang et al., 2001). Neurogenesis may play an important role in behavioral plasticity which may augment rehabilitation after injury (Shors et al., 2001). Therefore, drugs stimulating neurogenesis are urgently needed to reduce disability after damage. Interesting intravenous administration of NO donor was shown to increase neurogenesis in
Concluding remarks
The proposed neuroprotective mechanisms of NO and GSNO are illustrated in Fig. 2. With low nanomolar concentrations, NO activates guanylate cyclase, leading to cGMP-mediated up-regulation of thioredoxin and thioredoxin peroxidase enzymes. Moreover, up-regulation of thioredoxin system leads to removal of H2O2, repair of oxidized proteins, and up-regulation of Mn-superoxide dismutase enzyme, all of which resist oxidative stress and injury. NO-mediated up-regulation of thioredoxin, Bcl-2, and
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