Erythropoietin plus insulin-like growth factor-I protects against neuronal damage in a murine model of human immunodeficiency virus-associated neurocognitive disorders.

Objective: Prolonged human immunodeficiency virus-1 (HIV-1) infection leads to neurological debilitation, including motor dysfunction and frank dementia. Although pharmacological control of HIV infection is now possible, HIV-associated neurocognitive disorders (HAND) remain intractable. Here, we report that chronic treatment with erythropoietin (EPO) and insulin-like growth factor-1 (IGF-I) protects against HIV/gp120-mediated neuronal damage in culture and in vivo. Methods: Initially, we tested the neuroprotective effects of various concentrations of EPO, IGF-I, or EPO+IGF-1 from gp120-induced damage in vitro. To assess the chronic effects of EPO+IGF-1 administration in vivo, we treated HIV/gp120-transgenic or wild-type mice transnasally once a week for 4 months and subsequently conducted immunohistochemical analyses. Results: Low concentrations of EPO+IGF-1 provided neuroprotection from gp120 in vitro in a synergistic fashion. In vivo, EPO+IGF-1 treatment prevented gp120-mediated neuronal loss, but did not alter microgliosis or astrocytosis. Strikingly, in the brains of both humans with HAND and gp120-transgenic mice, we found evidence for hyperphosphorylated tau protein (paired helical filament-1 tau), which has been associated with neuronal damage and loss. In the mouse brain following transnasal treatment with EPO+IGF-1, in addition to neuroprotection we observed increased phosphorylation/activation of Akt (protein kinase B) and increased phosphorylation/inhibition of glycogen synthase kinase (GSK)-3/3, dramatically decreasing downstream hyperphosphorylation of tau. These results indicate that the peptides affected their cognate signaling pathways within the brain parenchyma. Interpretation: Our findings suggest that chronic combination therapy with EPO+IGF-1 provides neuroprotection in a mouse model of HAND, in part, through cooperative activation of phosphatidylinositol 3-kinase/Akt/GSK-3t3 signaling. This combination peptide therapy should therefore be tested in humans with HAND. ANN NEUROL 2010;68:342-352