It is becoming increasingly clear that HIV-1 infection and drug abuse are interlinked epidemics. In fact, cocaine, often abused by HIV-infected patients, has been suggested to hasten as well as worsen disease pathogenesis. HIV-1-associated neurological disorders (HAND) are primarily a result of increased influx of activated/infected monocytes from the periphery, in response to a chemokine gradient in the CNS. Among the known chemokines involved in this process, MCP-1 is known to correlate positively with HAND. Intriguingly, in our preliminary studies we have identified this chemokine as a key mediator that is up-regulated in both microglial cell line (BV-2) and in rat primary microglia that are exposed to cocaine. This effect is mediated through the cognate receptor for cocaine, the sigma receptor. We therefore hypothesized that cocaine-mediated enhancement of vascular changes in the CNS was involved in activation of sigma receptor leading to induction of MCP-1. To address this hypothesis two specific aims are proposed: 1) Investigate the molecular mechanisms involved in regulation of MCP-1 in microglia exposed to cocaine and, 2) Test the therapeutic potential of sigma receptor antagonist as an intervention strategy in vivo using the HIV Tat transgenic model of HIV neurodegeneration exposed to cocaine. These studies are both novel and innovative in that the efficacy of sigma receptor in abrogating monocyte migration can be of value not only for HAND but can be applicable to other neurodegenerative diseases as well.

Public Health Relevance

HIV-1infected individuals that abuse cocaine have increased risk of vascular changes that can result in complications of the CNS. This study proposes to explore how cocaine abuse can lead to increased neuroinflammation, and subsequently, to develop therapeutic intervention to inhibit inflammation.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-AARR-F (02))
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Purohit, Vishnudutt
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University of Nebraska Medical Center
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Yao, Honghong; Bethel-Brown, Crystal; Niu, Fang et al. (2014) Yin and Yang of PDGF-mediated signaling pathway in the context of HIV infection and drug abuse. J Neuroimmune Pharmacol 9:161-7
Yao, Honghong; Ma, Rong; Yang, Lu et al. (2014) MiR-9 promotes microglial activation by targeting MCPIP1. Nat Commun 5:4386
Costa, Blaise Mathias; Yao, Honghong; Yang, Lu et al. (2013) Role of endoplasmic reticulum (ER) stress in cocaine-induced microglial cell death. J Neuroimmune Pharmacol 8:705-14
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Yao, Honghong; Buch, Shilpa (2012) Rodent models of HAND and drug abuse: exogenous administration of viral protein(s) and cocaine. J Neuroimmune Pharmacol 7:341-51
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Yao, Honghong; Duan, Ming; Buch, Shilpa (2011) Cocaine-mediated induction of platelet-derived growth factor: implication for increased vascular permeability. Blood 117:2538-47
Yao, Honghong; Duan, Ming; Hu, Guoku et al. (2011) Platelet-derived growth factor B chain is a novel target gene of cocaine-mediated Notch1 signaling: implications for HIV-associated neurological disorders. J Neurosci 31:12449-54
Yao, Honghong; Kim, Keejun; Duan, Ming et al. (2011) Cocaine hijacks ?1 receptor to initiate induction of activated leukocyte cell adhesion molecule: implication for increased monocyte adhesion and migration in the CNS. J Neurosci 31:5942-55

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