Insulin‐like growth factor‐I–forkhead box O transcription factor 3a counteracts high glucose/tumor necrosis factor‐α‐mediated neuronal damage: Implications for human immunodeficiency virus encephalitis

Abstract

In HIV patients, antiretroviral medications trigger metabolic abnormalities, including insulin resistance. In addition, the inflammatory cytokine tumor necrosis factor-α (TNFα), 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 TNFα, HG-treated 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-treated neuronal cultures, accompanied by partial loss of mitochondrial potential and gradual retraction of neuronal processes. Addition of TNFα to HG-treated neurons increased expression of the FOXO-dependent proapoptotic gene Bim, which resulted in extensive apoptotic death. Insulin-like growth factor-I (IGF-I) significantly lowered intracellular ROS, which was accompanied by IGF-I-mediated FOXO3a nuclear export and decrease in its transcriptional activity. The clinical relevance of these findings is supported by detection of nuclear FOXO3a in TUNEL-positive cortical neurons from HIVE, especially in brain areas characterized by elevated TNFα.

Erythropoietin and Wnt1 Govern Pathways of mTOR, Apaf-1, and XIAP in Inflammatory Microglia

“…Loss of mitochondrial permeability leads to cytochrome c release and the induction of apoptotic and autophagic cascades [2, 61, 62, 66, 113–118]. We illustrate that both EPO and Wnt1 can block mitochondrial membrane depolarization and the release of cytochrome c, similar to prior studies with EPO [38, 41, 67, 101, 119] or Wnt1 [15, 38, 46].…”

Forkhead box A1 (FOXA1) is a key mediator of insulin‐like growth factor I (IGF‐I) activity

“…Previous studies have shown that insulin and IGF-I have the ability to regulate the transcriptional activity of forkhead family members, resulting in either activation or repression of forkhead target genes [Duncan et al, 1998; Jag et al, 2009; Wilk et al, 2011; Wolfrum et al, 2003]. In this study, we have reported a novel role for FOXA1 as a mediator of IGF-I-regulated target gene expression (Fig.…”

“…Additionally, IGF-I has been shown to regulate forkhead member FOXO3a [Wilk et al, 2011]. Therefore, we predicted that FOXA1 may be important in the regulation of IGF-I target genes and that IGF-I may be able to regulate FOXA1, due to the redundancy in insulin and IGF-I action and signal transduction pathways [Pollak, 2008; Zapf et al, 1984].…”

“…Although current literature only reveals a role for insulin-mediated signal transduction in the regulation of FOXA1, it is important to note that insulin and IGF-I share a high degree of sequence homology as well as the ability to regulate the same downstream signaling cascades, in particular activation of PI3K and MAPK pathways [Pollak, 2008; Zapf et al, 1984]. Additionally, it has recently been shown that IGF-I and insulin, through activation of the AKT signaling cascade, can both mediate the nuclear localization and transcriptional activity of FOXO3a, another member of the forkhead box family [Jag et al, 2009; Wilk et al, 2011; Zheng et al, 2000]. …”

Impairment of insulin receptor substrate 1 signaling by insulin resistance inhibits neurite outgrowth and aggravates neuronal cell death

“…Neurite outgrowth, which is involved in cognitive function (Singh et al, 2012), is also impaired in the brains of HFD-fed animals (Hashikawa-Hobara et al, 2012). Moreover, it is known that insulin signaling is related both to impaired memory function in diabetic dementia (Grote et al, 2011) and to neuronal apoptosis (Wilk et al, 2011). However, the details of the mechanism by which the cellular protective effects of IRS-1-mediated insulin signaling arise in neuronal cells under conditions of I/R have not been fully elucidated until now.…”