Our laboratory and others have proposed that neurodegeneration as a consequence of HIV-1 infection in the brain is predominantly dependent on the release of toxins by HIV-infected or gp120-activated microglia and macrophages. These toxins produce an excitotoxic injury via oxidative/nitrosative stress, and result in neuropathological changes, including dendritic injury, synaptic damage, and neuronal apoptosis. In attempting to prevent this type of HIV-related neurotoxicity, we discovered that erythropoietin (EPO), normally thought to be a kidney-generated cytokine, is made in the brain and is neuroprotective. Additionally, we and others found that insulin-like growth factor-I (IGF-I) is also neuroprotective. Here we report our preliminary data that EPO and IGF-I can prevent neuronal damage due to gp120 in a synergistic fashion in vitro, we demonstrate the likely molecular mechanism for this neuroprotective synergy, and we propose to study this effect in the HIV/gp 120-transgenic mouse as in vivo proof-of-principle to expedite human clinical trials with these clinically-tolerated agents.
Specific Aims : 1. To assess the possible neuroprotective effect of EPO in the HIV/gp120 transgenic mouse model. Hypothesis Tested: EPO protects neurons from HIV-related neuronal damage via a phosphoinositide (PI) 3 kinase/Akt (protein kinase B)-mediated transduction pathway acting, at least in part, through glycogen synthase kinase 3beta (GSK3beta) to prevent the hyperphosphorylation of tan. In contrast to EPO, gp120 decreases Akt phosphorylation. 2. To assess the possible neuroprotective effect of IGF-I in the HIV/gp120 transgenic mouse model. Hypothesis Tested: IGF-I also protects neurons via the PI3 kinase/Akt-mediated transduction pathway acting, at least in part, through GSK3beta to prevent the hyperphosphorylation of tau. 3. To assess the possible synergistic neuroprotective effect of EPO+IGF-I in the HIV/gp120 transgenic mouse model. Hypothesis Tested: EPO+IGF-I act synergistically to activate the anti-apoptotic PI3 kinase/Akt signaling pathway, and thus provide a synergistic degree of neuroprotection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS047973-01A1
Application #
6844449
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Nunn, Michael
Project Start
2004-08-15
Project End
2009-05-31
Budget Start
2004-08-15
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$397,519
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Banerjee, Sugato; Liao, Lujian; Russo, Rossella et al. (2012) Isobaric tagging-based quantification by mass spectrometry of differentially regulated proteins in synaptosomes of HIV/gp120 transgenic mice: implications for HIV-associated neurodegeneration. Exp Neurol 236:298-306
Kang, Yeon-Joo; Digicaylioglu, Murat; Russo, Rossella et al. (2010) Erythropoietin plus insulin-like growth factor-I protects against neuronal damage in a murine model of human immunodeficiency virus-associated neurocognitive disorders. Ann Neurol 68:342-52
Okamoto, Shu-ichi; Kang, Yeon-Joo; Brechtel, Christopher W et al. (2007) HIV/gp120 decreases adult neural progenitor cell proliferation via checkpoint kinase-mediated cell-cycle withdrawal and G1 arrest. Cell Stem Cell 1:230-6
Alirezaei, Mehrdad; Watry, Debbie D; Flynn, Claudia F et al. (2007) Human immunodeficiency virus-1/surface glycoprotein 120 induces apoptosis through RNA-activated protein kinase signaling in neurons. J Neurosci 27:11047-55
Yuan, H; Gerencser, A A; Liot, G et al. (2007) Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons. Cell Death Differ 14:462-71
Barsoum, Mark J; Yuan, Hua; Gerencser, Akos A et al. (2006) Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J 25:3900-11
Kaul, M; Lipton, S A (2005) Experimental and potential future therapeutic approaches for HIV-1 associated dementia targeting receptors for chemokines, glutamate and erythropoietin. Neurotox Res 8:167-86
Gu, Z; Nakamura, T; Yao, D et al. (2005) Nitrosative and oxidative stress links dysfunctional ubiquitination to Parkinson's disease. Cell Death Differ 12:1202-4
Helton, Rob; Cui, Jiankun; Scheel, John R et al. (2005) Brain-specific knock-out of hypoxia-inducible factor-1alpha reduces rather than increases hypoxic-ischemic damage. J Neurosci 25:4099-107