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-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)-3beta, dramatically decreasing downstream hyperphosphorylation of tau. These results indicate that the peptides affected their cognate signaling pathways within the brain parenchyma.


CONCLUSIONS
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-3beta signaling. This combination peptide therapy should therefore be tested in humans with HAND.
Kang
Yeon-Joo
YJ
Del E Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
Digicaylioglu
Murat
M
Russo
Rossella
R
Kaul
Marcus
M
Achim
Cristian L
CL
Fletcher
Lauren
L
Masliah
Eliezer
E
Lipton
Stuart A
SA
D000281:Administration, Intranasal; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004921:Erythropoietin / Q000627:therapeutic use*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009830:Olfactory Bulb / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D016875:tau Proteins / Q000378:metabolism
D002867:Chromones; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D009025:Morpholines; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D016875:tau Proteins; D004921:Erythropoietin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007334:Insulin-Like Growth Factor I; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
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