Peroxynitrite induces neuronal cell death in aging and age-associated disorders: A review

Peroxynitrite produced from nitric oxide and superoxide has been proposed t o cause neuronal dysfunction and cell death in aging and age-related degene rative diseases. 3-Nitrotyosine, an oxidation product of tyrosine by peroxy nitrite, was reported to increase in degenerating brains. In this paper, in volvement of peroxynitrite in neuronal cell death was studied by analyses o f human brains and in vitro experiments on cell death induced by a peroxyni trite-generating agent, SIN-1. 3-Nitrotyrosine-containing proteins were det ected in lipofuscin, a typical aging-related pigment in human brains. The c ytotoxicity of peroxynitrite was examined in human dopaminergic SH-SY5Y cel ls by use of SIN-1. SIN-1 induced apoptotic cell death in the cells, and in creased the level of 3-nitrotyrosine-containing proteins. The intracellular transduction of death signal was studied in apoptosis induced by peroxynit rite, Apoptosis was induced by sequential death cascade, collapse of mitoch ondrial membrane potential, activation of caspases and fragmentation of nuc lear DNA, In addition, phosphorylation of p38 mitogen activated phosphokina se(MAPK) was found to be associated with apoptosis by SIN-1, as shown by in hibition of apoptotic process by SB202190, a p38 inhibitor. Involvement of peroxynitrite in the cell death is discussed in relation to neuronal degene ration in aging and age-associated diseases.