| Publication Abstract Display | | Type: Published Abstract | | Title: Transnasal erythropoietin (EPO) plus insulin-like growth factor-1 (IGF-1) protect against neuronal damage in a murine transgenic model of HIV-associated dementia (HAD). | | Authors: Kang YL, "Russo R, Kaul M, Masliah E, Lipton SA.
" | | Year: 2008 | | Publication: Society for Neuroscience Abstracts | | Volume: 653.7 Issue: Pages: | | Abstract:Infection with human immunodeficiency virus-1 (HIV-1) can cause severe and debilitating neurological problems, including behavioral abnormalities, motor dysfunction and frank dementia. Although there have been major improvements in the control of systemic viral infection, no effective therapy for HAD currently exists. Here, we report that chronic treatment with EPO plus IGF-I provides protection against HIV/gp120-mediated neuronal damage in cultures and in vivo. To assess the chronic effects of EPO+IGF-I administration in vivo, we treated HIV/gp120 transgenic or wild-type (WT) mice transnasally once a week for 3 months, and subsequently conducted immunohistochemical analysis. EPO+IGF-I treatment prevented neuronal damage mediated by the HIV-1 coat protein gp120, but did not alter microgliosis or astrocytosis. Strikingly, in the brains of both humans with HAD and HIV/gp120 transgenic mice, we found evidence for hyperphosphorylated tau protein (PHF-I tau), which has been associated with neuronal damage and loss in other neurological diseases. In the gp120 mouse model, we found that transnasal treatment with EPO+IGF-I increased phosphorylation of Akt and GSK-3β, apparently contributing to a dramatic decrease in tau hyperphosphorylation in the brain; these results also indicate that the peptides affected their cognate signaling pathways within the brain parenchyma. Our findings suggest that chronic combination therapy of EPO+IGF-I provides neuroprotection, in part, through cooperative activation of phosphatidylinositol 3-kinase (PI3K)/Akt and GSK-3β signaling (Digicaylioglu and Lipton, Nature 2001; Digicaylioglu et al., PNAS 2004), and suggest that this combination may serve as an effective therapeutic for HAD. |
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