Neuronal protection and destruction by NO

Abstract

Nitric oxide (NO)-related species include different redox states of the NO group, which have recently been reported to exist endogenously in biological tissues including the brain. The importance of these different NO-related species is that their distinct chemical reactivities can influence the life and death of neurons in response to various insults. In the case of NO + equivalents (having one less electron than NO . ), the mechanism of reaction often involves Snitrosylation or transfer of the NO group to the sulfhydryl of a cysteine residue (or more properly to a thiolate anion) to form an RS-NO; further oxidation of critical thiols can possibly then form disulfide bonds from neighboring cysteine residues. We have mounted both physiological and chemical evidence that N-methyl-D-aspartate receptor (NMDAR) activity and caspase enzyme activity can be decreased by S-nitrosylation, as can other signaling molecules involved in neuronal apoptotic pathways, to afford neuroprotection. Over the past 5 years, beginning with our report on the NMDAR, evidence has accumulated that S-nitrosylation can regulate the biological activity of a great variety of proteins, in some ways akin to phosphorylation. Thus, this chemical reaction is gaining acceptance as a newly-recognized molecular switch to control protein function via reactive thiol groups, such as those encountered on the NMDAR and in the active site of caspases. One method of producing S-nitrosylation of the NMDAR and caspases is the administration of nitroglycerin, and nitroglycerin can be neuroprotective in acute focal ischemia/reperfusion models via mechanisms other than increasing cerebral blood flow. In contrast, NO . itself does not appear to react with thiol under physiological conditions. In fact, the favored reaction of NO . is with O 2 .7 (superoxide anion) to form ONOO 7 (peroxynitrite), which can lead to neurotoxicity. A third NO-related species with one added electron compared to NO . is nitroxyl anion (NO 7 ). NO 7 ± unlike NO . but reminiscent of NO + transfer ± reacts with critical thiol groups of the NMDA receptor to curtail excessive Ca 2+ influx and thus provide neuroprotection from excitotoxic insults.

Specific pattern of p53 phosphorylation during nitric oxide-induced cell cycle arrest

“…NO, produced in the organism by a family of NO synthases (NOS), has been implicated in the regulation of blood pressure, immunity, and neurotransmission (Bredt and Snyder, 1994;Nathan and Xie, 1994;Stamler, 1994;Garthwaite and Boulton, 1995). It is also critically involved in many pathological responses, such as in¯ammation, septic shock, and neurotoxicity (Gross and Wolin, 1995;Nicotera et al, 1999;Lipton, 1999). Furthermore, NO can aect cell division, programmed cell death, or acquisition of dierentiated phenotype (Peunova and Enikolopov, 1995;Kuzin et al, 1996;Enikolopov et al, 1999;Papapetropoulos et al, 1997;Poluha et al, 1997;Ishida et al, 1997;Mannick et al, 1997;Forrester et al, 1996;Messmer and Brune, 1996;Brune et al, 1998;Gibbs and Truman, 1998;Wingrove and O'Farrell, 1999).…”

“…Some of the long lasting eects of NO may be related to its ability to act as a potent regulator of proliferation: exogenously added NO can reversibly suppress DNA synthesis and progression through the various phases of the cell cycle (Stamler, 1994;Garg and Hassid, 1990;Lepoivre et al, 1990;Kwon et al, 1991), and can induce or suppress programmed cell death in particular cell types (Nicotera et al, 1999;Lipton, 1999;Mannick et al, 1997;Brune et al, 1998). It has been further speculated that part of the action of NO as a signaling molecule re¯ects its highly reactive nature and its potential, at high concentrations, to modify and damage DNA Tamir et al, 1996); however, the relevance of this feature of NO to its action in vivo is still unclear.…”

Prevention of Peroxynitrite-induced Apoptosis of Motor Neurons and PC12 Cells by Tyrosine-containing Peptides

“…In inflammatory pathological conditions, the increased production of nitric oxide and superoxide boosts the generation of reactive oxygen and nitrogen species, including peroxynitrite (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Peroxynitrite is a strong oxidant formed by the diffusion-limited reaction of superoxide and nitric oxide (11,12).…”

Thioredoxin participates in a cell death pathway induced by interferon and retinoid combination

“…Consistent with our studies evidence for redox regulation of caspase functions has been recently reported. For example, nitric oxide-mediated oxidation and S-nitrosylation of active site cysteine have been implicated in inhibition of caspase-3 activity (Lipton, 1999;Mohr et al, 1997). Depletion of cellular glutathione levels enhances the apoptotic e ect of TNF-a in certain hepatoma cells (Pierce et al, 2000).…”