Document Detail


Erythropoietin plus insulin-like growth factor-I protects against neuronal damage in a murine model of human immunodeficiency virus-associated neurocognitive disorders.
MedLine Citation:
PMID:  20818790     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
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-3beta signaling. This combination peptide therapy should therefore be tested in humans with HAND.
Authors:
Yeon-Joo Kang; Murat Digicaylioglu; Rossella Russo; Marcus Kaul; Cristian L Achim; Lauren Fletcher; Eliezer Masliah; Stuart A Lipton
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Annals of neurology     Volume:  68     ISSN:  1531-8249     ISO Abbreviation:  Ann. Neurol.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-06     Completed Date:  2010-09-24     Revised Date:  2013-08-22    
Medline Journal Info:
Nlm Unique ID:  7707449     Medline TA:  Ann Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  342-52     Citation Subset:  IM    
Affiliation:
Del E Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
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MeSH Terms
Descriptor/Qualifier:
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
HIV Envelope Protein gp120 / genetics
HIV Infections / drug therapy*,  metabolism,  pathology
Humans
Immunoprecipitation / methods
Insulin-Like Growth Factor I / therapeutic use*
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 / drug effects
Rats
tau Proteins / metabolism
Grant Support
ID/Acronym/Agency:
MH072529/MH/NIMH NIH HHS; MH076681/MH/NIMH NIH HHS; P30 NS057096/NS/NINDS NIH HHS; R01 EY009024/EY/NEI NIH HHS; R01 EY09024/EY/NEI NIH HHS; R01 NS043242/NS/NINDS NIH HHS; R01 NS046994/NS/NINDS NIH HHS; R01 NS046994/NS/NINDS NIH HHS; R01 NS047973/NS/NINDS NIH HHS; R01 NS047973/NS/NINDS NIH HHS; R01 NS050621/NS/NINDS NIH HHS; R01 NS43242/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Chromones; 0/Enzyme Inhibitors; 0/HIV Envelope Protein gp120; 0/Morpholines; 0/Nerve Tissue Proteins; 0/Neuroprotective Agents; 0/tau Proteins; 11096-26-7/Erythropoietin; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3
Comments/Corrections

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