title: Erythropoietin plus insulin-like growth factor-I protects against neuronal damage in a murine model of human immunodeficiency virus-associated neurocognitive disorders.
abstract: 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.
authors.affiliation: Del E Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Yeon-Joo
authors.initials: YJ
authors.lastname: Kang
authors.forename: Murat
authors.initials: M
authors.lastname: Digicaylioglu
authors.forename: Rossella
authors.initials: R
authors.lastname: Russo
authors.forename: Marcus
authors.initials: M
authors.lastname: Kaul
authors.forename: Cristian L
authors.initials: CL
authors.lastname: Achim
authors.forename: Lauren
authors.initials: L
authors.lastname: Fletcher
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: 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
chemical_list: 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
references.citation: Endocrinology. 1994 Nov;135(5):1753-61
references.pmid: 7525251
references.citation: Diabetes. 1994 Mar;43(3):369-74
references.pmid: 8314009
references.citation: Neuron. 1999 Nov;24(3):751-62
references.pmid: 10595524
references.citation: J Neurol Sci. 2001 Jun 15;187(1-2):91-7
references.pmid: 11440750
references.citation: Neuroscience. 2004;127(2):481-96
references.pmid: 15262337
references.citation: Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8212-6
references.pmid: 10393974
references.citation: Lancet. 1988 Jan 16;1(8577):97-100
references.pmid: 2891990
references.citation: Clin Lab Med. 2002 Sep;22(3):703-17
references.pmid: 12244593
references.citation: J Neurosci. 2005 Sep 14;25(37):8375-85
references.pmid: 16162919
references.citation: Neuroscience. 1997 Jan;76(1):105-16
references.pmid: 8971763
references.citation: Blood. 2005 Oct 1;106(7):2382-90
references.pmid: 15961516
references.citation: J Biol Chem. 1997 May 2;272(18):11671-3
references.pmid: 9115213
references.citation: Clin Investig. 1994;72(6 Suppl):S36-43
references.pmid: 7950171
references.citation: AIDS. 2007 Sep 12;21(14):1877-86
references.pmid: 17721095
references.citation: J Neurosurg. 2009 Jul;111(1):164-70
references.pmid: 19284235
references.citation: J Neuropathol Exp Neurol. 1994 May;53(3):231-8
references.pmid: 8176406
references.citation: J Immunol. 2007 Oct 1;179(7):4345-56
references.pmid: 17878329
references.citation: Neuroreport. 2004 Apr 9;15(5):761-3
references.pmid: 15073510
references.citation: Nat Cell Biol. 2007 Feb;9(2):139-48
references.pmid: 17187063
references.citation: Neuron. 2003 Oct 30;40(3):471-83
references.pmid: 14642273
references.citation: J Neuropathol Exp Neurol. 1999 Sep;58(9):1010-9
references.pmid: 10499443
references.citation: Nature. 1994 Jan 13;367(6459):188-93
references.pmid: 8114918
references.citation: Am J Pathol. 1995 May;146(5):1121-30
references.pmid: 7747806
references.citation: Metab Brain Dis. 2004 Dec;19(3-4):195-206
references.pmid: 15554415
references.citation: J Cell Sci. 2004 Nov 15;117(Pt 24):5721-9
references.pmid: 15537830
references.citation: J Pain Symptom Manage. 2004 Feb;27(2):185-90
references.pmid: 15157043
references.citation: J Neurosci. 2005 Dec 14;25(50):11542-52
references.pmid: 16354912
references.citation: Nature. 2001 Aug 9;412(6847):641-7
references.pmid: 11493922
references.citation: J Neurosci. 2000 Jan 15;20(2):2-8
references.pmid: 10632601
references.citation: J Clin Invest. 1996 Feb 1;97(3):789-98
references.pmid: 8609236
references.citation: J Neurosci Res. 2000 Feb 1;59(3):332-41
references.pmid: 10679768
references.citation: Nat Med. 2006 Jul;12(7):764-5; discussion 765
references.pmid: 16829938
references.citation: Trends Neurosci. 1997 Aug;20(8):326-31
references.pmid: 9246719
references.citation: Biochem J. 1997 May 1;323 ( Pt 3):577-91
references.pmid: 9169588
references.citation: Pharm Res. 2007 Sep;24(9):1729-32
references.pmid: 17629776
references.citation: Nat Neurosci. 2002 Jun;5(6):514-6
references.pmid: 11992114
references.citation: Nature. 2001 Apr 19;410(6831):988-94
references.pmid: 11309629
references.citation: J Neuroimmunol. 2004 Dec;157(1-2):3-10
references.pmid: 15579274
references.citation: J Neurosci. 2002 May 15;22(10):4015-24
references.pmid: 12019321
references.citation: Nat Rev Neurosci. 2005 Jun;6(6):484-94
references.pmid: 15928718
references.citation: J Neurosci. 2007 Feb 21;27(8):1981-91
references.pmid: 17314294
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10526-31
references.pmid: 10984541
references.citation: AIDS. 2005 Mar 4;19(4):407-11
references.pmid: 15750394
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9855-60
references.pmid: 15210945
references.citation: J Neurosci Res. 2008 Feb 1;86(2):243-55
references.pmid: 17847079
references.citation: J Clin Endocrinol Metab. 1994 Aug;79(2):470-9
references.pmid: 7519191
references.citation: Kidney Int. 1994 Jul;46(1):201-7
references.pmid: 7933838
references.citation: Science. 2001 Jul 27;293(5530):711-4
references.pmid: 11408621
references.citation: J Neurosci Res. 2004 Apr 1;76(1):98-103
references.pmid: 15048933
references.citation: Neurosci Lett. 2005 Oct 14;387(1):5-10
references.pmid: 16054296