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Such alterations are also associated with inhibition of cytochrome c oxidase activity and microtubule network disassembly, which are considered hallmarks of nitric oxide (NO) toxicity. In neuroblastoma cells, BSO treatment also induces cell proliferation arrest through the ERK1\/2-p53 pathway that finally results in caspase-independent apoptosis, as evident from the translocation of apoptosis-inducing factor from mitochondria towards nuclei. A deeper analysis of the signaling processes indicates that the NO-cGMP pathway is involved in cell proliferation arrest and death. In fact, these events are completely reversed by L-NAME, a specific NO synthase inhibitor, indicating that NO, rather than the depletion of GSH per se, is the primary mediator of cell damage. In addition, the guanylate cyclase (GC) inhibitor LY83583 is able to completely block activation of ERK1\/2 and counteract BSO toxicity. In cortical neurons, NMDA (N-methyl-D-aspartic acid) treatment results in GSH decrease and BSO-mediated NO cytotoxicity is enhanced by either epidermal growth factor (EGF) or NMDA. These findings support the idea that GSH might represent the most important buffer of NO toxicity in neuronal cells, and indicate that the disruption of cellular redox buffering controlled by GSH makes neuronal cells susceptible to endogenous physiological flux of NO.<\/jats:p>","DOI":"10.1242\/jcs.077149","type":"journal-article","created":{"date-parts":[[2011,3,2]],"date-time":"2011-03-02T08:25:31Z","timestamp":1299054331000},"page":"1043-1054","source":"Crossref","is-referenced-by-count":58,"title":["Nitric oxide is the primary mediator of cytotoxicity induced by GSH depletion in neuronal cells"],"prefix":"10.1242","volume":"124","author":[{"given":"Katia","family":"Aquilano","sequence":"first","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Baldelli","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele \u2018La Pisana\u2019, Via dei Bonacolsi, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Cardaci","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Rotilio","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"IRCCS San Raffaele \u2018La Pisana\u2019, Via dei Bonacolsi, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosa","family":"Ciriolo","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"IRCCS San Raffaele \u2018La Pisana\u2019, Via dei Bonacolsi, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042521505007800_R1","doi-asserted-by":"crossref","first-page":"3222","DOI":"10.1021\/pr900039c","article-title":"Protein tyrosine nitration: selectivity, physicochemical and biological consequences, denitration, and proteomics methods for the identification of tyrosine-nitrated proteins","volume":"8","author":"Abello","year":"2009","journal-title":"J. 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