title: Nitric oxide and neuronal death.
abstract: NO and its derivatives can have multiple effects, which impact on neuronal death in different ways. High levels of NO induces energy depletion-induced necrosis, due to: (i) rapid inhibition of mitochondrial respiration, (ii) slow inhibition of glycolysis, (iii) induction of mitochondrial permeability transition, and/or (iv) activation of poly-ADP-ribose polymerase. Alternatively, if energy levels are maintained, NO can induce apoptosis, via oxidant activation of: p53, p38 MAPK pathway or endoplasmic reticulum stress. Low levels of NO can block cell death via cGMP-mediated: vasodilation, Akt activation or block of mitochondrial permeability transition. High NO may protect by killing pathogens, activating NF-kappaB or S-nitro(sy)lation of caspases and the NMDA receptor. GAPDH, Drp1, mitochondrial complex I, matrix metalloprotease-9, Parkin, XIAP and protein-disulphide isomerase can also be S-nitro(sy)lated, but the contribution of these reactions to neurodegeneration remains unclear. Neurons are sensitive to NO-induced excitotoxicity because NO rapidly induces both depolarization and glutamate release, which together activate the NMDA receptor. nNOS activation (as a result of NMDA receptor activation) may contribute to excitotoxicity, probably via peroxynitrite activation of poly-ADP-ribose polymerase and/or mitochondrial permeability transition. iNOS is induced in glia by inflammation, and may protect; however, if there is also hypoxia or the NADPH oxidase is active, it can induce neuronal death. Microglial phagocytosis may contribute actively to neuronal loss.
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, United Kingdom. gcb@mole.bio.cam.ac.uk
authors.forename: Guy C
authors.initials: GC
authors.lastname: Brown
mesh_terms: D000818:Animals; D016923:Cell Death; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*
chemical_list: D009569:Nitric Oxide