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Here, we explored the mechanism by which NO, produced from the NO donor <jats:italic>S<\/jats:italic>\u2010nitroso\u2010acetyl\u2010<jats:sc>d<\/jats:sc>\u2010<jats:sc>l<\/jats:sc>\u2010penicillamine (SNAP), exerts its neuroprotective effect in purified cultures of chick retinal neurons. Cultures prepared from 8\u2010day\u2010old chick embryo retinas and incubated for 24\u2003h (1\u2003day in culture, C1) were treated or not with SNAP, incubated for a further 72\u2003h (up to 4\u2003days in culture, C4), fixed, and the number of cells estimated, or processed for cell death estimation, by measuring the reduction of the metabolic dye 3\u2010(4,5\u2010dimethylthiazol\u20102\u2010yl)\u20102,5\u2010diphenyltetrazolium bromide (MTT). Experimental cultures were run in parallel but were re\u2010fed with fresh medium in the absence or presence of SNAP at culture day 3 (C3), incubated for a further 24\u2003h up to C4, then fixed or processed for the MTT assay. Previous studies showed that the re\u2010feeding procedure promotes extensive cell death. SNAP prevented this death in a concentration\u2010 and time\u2010dependent manner through the activation of soluble guanylate cyclase; this protection was significantly reversed by the enzyme inhibitors 1H\u2010[1,2,4]oxadiazolo\u2010[4,3\u2010a]quinoxalin\u20101\u2010one (ODQ) or LY83583, and mimicked by 8\u2010bromo cyclic guanosine 5\u2032\u2010phosphate (8Br\u2010cGMP) (GMP) or 3\u2010(5\u2032\u2010hydroxymethyl\u20102\u2032\u2010furyl)\u20101\u2010benzyl indazole (YC\u20101), guanylate cyclase activators. The effect was blocked by the NO scavenger 2\u2010phenyl\u20104,4,5,5\u2010tetramethylimidazoline\u20101\u2010oxyl\u20103\u2010oxide (PTIO). The effect of NO was also suppressed by LY294002, Wortmannin, PD98059, KN93 or H89, indicating the involvement, respectively, of phosphatidylinositol\u20103 kinase, extracellular\u2010regulated kinases, calmodulin\u2010dependent kinases and protein kinase A signaling pathways. NO also induced a significant increase of neurite outgrowth, indicative of neuronal differentiation, and blocked cell death induced by hydrogen peroxide. Cyclosporin A, an inhibitor of the mitochondrial permeability transition pore considered an important mediator of apoptosis and necrosis, as well as boc\u2010aspartyl (OMe) fluoromethylketone (BAF), a caspase inhibitor, also blocked cell death induced by re\u2010feeding the cultures. These findings demonstrate that NO inhibits apoptosis of retinal neurons in a cGMP\/protein kinase G (PKG)\u2010dependent way, and strengthens the notion that NO plays an important role during CNS development.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2006.04244.x","type":"journal-article","created":{"date-parts":[[2006,11,20]],"date-time":"2006-11-20T17:17:40Z","timestamp":1164043060000},"page":"382-394","source":"Crossref","is-referenced-by-count":39,"title":["Nitric oxide regulates cell survival in purified cultures of avian retinal neurons: involvement of multiple transduction pathways"],"prefix":"10.1111","volume":"100","author":[{"given":"T. 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