|Erythropoietin plus insulin-like growth factor-I protects against neuronal damage in a murine model of human immunodeficiency virus-associated neurocognitive disorders.|
|PMID: 20818790 Owner: NLM Status: MEDLINE|
|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.
|Yeon-Joo Kang; Murat Digicaylioglu; Rossella Russo; Marcus Kaul; Cristian L Achim; Lauren Fletcher; Eliezer Masliah; Stuart A Lipton|
|Type: Journal Article; Research Support, N.I.H., Extramural|
|Title: Annals of neurology Volume: 68 ISSN: 1531-8249 ISO Abbreviation: Ann. Neurol. Publication Date: 2010 Sep|
|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|
|Languages: eng Pagination: 342-52 Citation Subset: IM|
|Del E Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.|
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Apoptosis / drug effects
Cerebral Cortex / cytology
Chromones / pharmacology
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Enzyme-Linked Immunosorbent Assay / methods
Erythropoietin / therapeutic use*
Glycogen Synthase Kinase 3 / metabolism
HIV Envelope Protein gp120 / genetics
HIV Infections / drug therapy*, metabolism, pathology
Immunoprecipitation / methods
Insulin-Like Growth Factor I / therapeutic use*
Morpholines / pharmacology
Nerve Tissue Proteins / metabolism
Neuroglia / drug effects
Neurons / drug effects*
Neuroprotective Agents / therapeutic use*
Olfactory Bulb / drug effects
Phosphorylation / drug effects
tau Proteins / metabolism
|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|
|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 18.104.22.168/glycogen synthase kinase 3 beta; EC 22.214.171.124/Glycogen Synthase Kinase 3|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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