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

• Published in: Annals of neurology 2010-09, Vol.68 (3), p.342-352
• Main Authors: Kang, Yeon-Joo, Digicaylioglu, Murat, Russo, Rossella, Kaul, Marcus, Achim, Cristian L., Fletcher, Lauren, Masliah, Eliezer, Lipton, Stuart A.
• Format: Article
• Language: English
• Subjects: Administration, Intranasal; Adult; Animals; Apoptosis - drug effects; Cells, Cultured; Cerebral Cortex - cytology; Chromones - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Embryo, Mammalian; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay - methods; Erythropoietin - therapeutic use; Female; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; HIV; HIV Envelope Protein gp120 - genetics; HIV Infections - drug therapy; HIV Infections - metabolism; HIV Infections - pathology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Immunoprecipitation - methods; Insulin-Like Growth Factor I - therapeutic use; Insulin-like growth factors; Kinases; Male; Mice; Mice, Transgenic; Middle Aged; Morpholines - pharmacology; Nerve Tissue Proteins - metabolism; Neuroglia - drug effects; Neurons - drug effects; Neuroprotective Agents - therapeutic use; Olfactory Bulb - drug effects; Phosphorylation; Phosphorylation - drug effects; Rats; Rodents; tau Proteins - metabolism
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.22070

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‐I (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‐I from gp120‐induced damage in vitro. To assess the chronic effects of EPO+IGF‐I 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‐I provided neuroprotection from gp120 in vitro in a synergistic fashion. In vivo, EPO+IGF‐I 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‐I tau), which has been associated with neuronal damage and loss. In the mouse brain following transnasal treatment with EPO+IGF‐I, in addition to neuroprotection we observed increased phosphorylation/activation of Akt (protein kinase B) and increased phosphorylation/inhibition of glycogen synthase kinase (GSK)‐3β, 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‐I provides neuroprotection in a mouse model of HAND, in part, through cooperative activation of phosphatidylinositol 3‐kinase/Akt/GSK‐3β signaling. This combination peptide therapy should therefore be tested in humans with HAND. ANN NEUROL 2010;68:342–352