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LK\u2010induced cell death is blocked by GW5074 {5\u2010Iodo\u20103\u2010[(3,5\u2010dibromo\u20104\u2010hydroxyphenyl) methylene]\u20102\u2010indolinone}, a synthetic drug that inhibits c\u2010Raf activity <jats:italic>in\u2003vitro<\/jats:italic>. GW5074 has no direct effect on the activities of several apoptosis\u2010associated kinases when assayed <jats:italic>in\u2003vitro<\/jats:italic>. In contrast to its effect <jats:italic>in\u2003vitro<\/jats:italic>, treatment of neurons with GW5074 causes c\u2010Raf activation (when measured <jats:italic>in\u2003vitro<\/jats:italic> in the absence of the drug) and stimulates the Raf\u2010MEK\u2010ERK pathway. Treatment of neurons with GW5074 also leads to an increase in the activity of B\u2010Raf, which is not inhibited by GW5074 <jats:italic>in\u2003vitro<\/jats:italic> at concentrations at which the drug exerts its neuroprotective effect. PD98059 and U0126, two distinct inhibitors of MEK, block the activation of ERK by GW5074 but have no effect on its ability to prevent cell death. Overexpression of a dominant\u2010negative form of Akt does not reduce the efficacy of GW5074, demonstrating an Akt\u2010independent mechanism of action. Neuroprotection is inhibited by SN\u201050, a specific inhibitor of nuclear factor\u2010kappa B (NF\u2010\u03baB) and by the Ras inhibitor S\u2010<jats:italic>trans<\/jats:italic>, <jats:italic>trans<\/jats:italic>\u2010farnesylthiosalicylic acid (FTS) implicating NF\u2010\u03baB and Ras in the neuroprotective signaling pathway activated by GW5074. In addition to preventing LK\u2010induced apoptosis, treatment with GW5074 protects against the neurotoxic effects of MPP+ and methylmercury in cerebellar granule neurons, and glutathione depletion\u2010induced oxidative stress in cortical neurons. Furthermore, GW5074 prevents neurodegeneration and improves behavioral outcome in an animal model of Huntington's disease. Given its neuroprotective effect on distinct types of cultured neurons, in response to different neurotoxic stimuli, and in an animal model of neurodegeneration, GW5074 could have therapeutic value against neurodegenerative pathologies in humans.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2004.02530.x","type":"journal-article","created":{"date-parts":[[2004,7,16]],"date-time":"2004-07-16T08:31:03Z","timestamp":1089966663000},"page":"595-608","source":"Crossref","is-referenced-by-count":81,"title":["The c\u2010Raf inhibitor GW5074 provides neuroprotection <i>in\u2003vitro<\/i> and in an animal model of neurodegeneration through a MEK\u2010ERK and Akt\u2010independent mechanism"],"prefix":"10.1111","volume":"90","author":[{"given":"Paul C.","family":"Chin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley 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