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In addition, the inflammatory cytokine tumor necrosis factor\u2010\u03b1 (TNF\u03b1), which is elevated in human immunodeficiency virus encephalitis (HIVE), also induces insulin resistance and inflicts neuronal damage in vitro. In differentiated PC12 cells and rat cortical neurons, high glucose (HG; 25 mM) triggers reactive oxygen species (ROS) accumulation, contributing to the retraction of neuronal processes, with only a minimal involvement of neuronal apoptosis. In the presence of TNF\u03b1, HG\u2010treated neurons undergo massive apoptosis. Because mammalian homolog of the Forkhead family of transcription factors, Forkhead box O transcription factor 3a (FOXO3a), controls ROS metabolism, we asked whether FOXO3a could affect the fate of differentiated neurons in the paradigm of HIVE. We observed FOXO3a nuclear translocation in HG\u2010treated neuronal cultures, accompanied by partial loss of mitochondrial potential and gradual retraction of neuronal processes. Addition of TNF\u03b1 to HG\u2010treated neurons increased expression of the FOXO\u2010dependent proapoptotic gene Bim, which resulted in extensive apoptotic death. Insulin\u2010like growth factor\u2010I (IGF\u2010I) significantly lowered intracellular ROS, which was accompanied by IGF\u2010I\u2010mediated FOXO3a nuclear export and decrease in its transcriptional activity. The clinical relevance of these findings is supported by detection of nuclear FOXO3a in TUNEL\u2010positive cortical neurons from HIVE, especially in brain areas characterized by elevated TNF\u03b1. \u00a9 2010 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.22542","type":"journal-article","created":{"date-parts":[[2010,12,8]],"date-time":"2010-12-08T18:11:16Z","timestamp":1291831876000},"page":"183-198","source":"Crossref","is-referenced-by-count":22,"title":["Insulin\u2010like growth factor\u2010I\u2013forkhead box O transcription factor 3a counteracts high glucose\/tumor necrosis factor\u2010\u03b1\u2010mediated neuronal damage: Implications for human immunodeficiency virus 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