Review
Neuroprotective properties of nitric oxide and S-nitrosoglutathione

https://doi.org/10.1016/j.taap.2005.02.028Get rights and content

Abstract

Oxidative stress and apoptosis may play an important role in the neurodegeneration. The present paper outlines antioxidative and antiapototic mechanisms of nitric oxide and S-nitrosothiols, which could mediate neuroprotection. Nitric oxide generated by nitric oxide synthase or released from an endogenous S-nitrosothiol, S-nitrosoglutathione may up-regulate antioxidative thioredoxin system and antiapototic Bcl-2 protein through a cGMP-dependent mechanism. Moreover, nitric oxide radicals have been shown to have direct antioxidant effect through their reaction with free radicals and iron–oxygen complexes. In addition to serving as a stabilizer and carrier of nitric oxide, S-nitrosoglutathione may have protective effect through transnitrosylation reactions. Based on these new findings, a hypothesis arises that the homeostasis of nitric oxide, S-nitrosothiols, glutathione, and thioredoxin systems is important for protection against oxidative stress, apoptosis, and related neurodegenerative disorders.

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

References (48)

  • R. Radi et al.

    Peroxynitrite oxidation of sulfhydryls: the cytotoxic potential of superoxide and nitric oxide

    J. Biol. Chem.

    (1991)
  • P. Rauhala et al.

    Peroxidation of brain lipids in vitro: nitric oxide versus hydroxyl radical

    Free Radical Biol. Med.

    (1996)
  • H. Rubbo et al.

    Nitric oxide regulation of superoxide and peroxynitrite dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives

    J. Biol. Chem.

    (1994)
  • J.S. Stamler

    Redox signalling: nitrosylation and related target interactions of nitric oxide

    Cell

    (1994)
  • J.S. Stamler et al.

    Nitrosylation the prototypic redox-based signaling mechanism

    Cell

    (2001)
  • L. Tenneti et al.

    Supression of neuronal apoptosis by S-nitrosylation of caspases

    Neurosci. Lett.

    (1997)
  • D.A. Wink et al.

    Chemical biology of nitric oxide: insights into regulatory, cytotoxic and cytoprotective mechanisms of nitric oxide

    Free Radical Biol. Med.

    (1998)
  • D.A. Wink et al.

    The cytotoxicity of nitroxyl: possible implications for the pathophysiological role of NO

    Arch. Biochem. Biophys.

    (1998)
  • T. Andoh et al.

    Preconditioning regulation of bcl-2 and p66shc by human NOS1 enhances tolerance to oxidative stress

    FASEB J.

    (2000)
  • T. Andoh et al.

    Preconditioning-mediated neuroprotection: role of nitric oxide, cGMP, and new protein expression

    Ann. N. Y. Acad. Sci.

    (2002)
  • E.S. Arner et al.

    Physiological functions of thioredoxin and thioredoxin reductase

    Eur. J. Biochem.

    (2000)
  • J.S. Beckman et al.

    Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide

    Proc. Natl. Acad. Sci.

    (1990)
  • C.C. Chiueh

    Neuroprotective properties of nitric oxide

    Ann. N. Y. Acad. Sci.

    (1999)
  • C.C. Chiueh et al.

    The redox pathways of S-nitrosoglutahione, glutathione and nitric oxide in cell to neuron communication

    Free Radical Res.

    (1999)
  • Cited by (0)

    View full text