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Molecular Pharmacology

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Research ArticleArticle

Activation of Cannabinoid Type 2 Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

Hee Jung Kim, Angela H. Shin and Stanley A. Thayer
Molecular Pharmacology September 2011, 80 (3) 357-366; DOI: https://doi.org/10.1124/mol.111.071647
Hee Jung Kim
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Angela H. Shin
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Stanley A. Thayer
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Abstract

HIV-1 infection of the central nervous system is associated with dendritic and synaptic damage that correlates with cognitive decline in patients with HIV-1-associated dementia (HAD). HAD is due in part to the release of viral proteins from infected cells. Because cannabinoids modulate neurotoxic and inflammatory processes, we investigated their effects on changes in synaptic connections induced by the HIV-1 envelope glycoprotein gp120. Morphology and synapses between cultured hippocampal neurons were visualized by confocal imaging of neurons expressing DsRed2 and postsynaptic density protein 95 fused to green fluorescent protein (PSD95-GFP). Twenty-four-hour treatment with gp120 IIIB decreased the number of PSD95-GFP puncta by 37 ± 4%. The decrease was concentration-dependent (EC50 = 153 ± 50 pM). Synapse loss preceded cell death as defined by retention of DsRed2 fluorescence gp120 activated CXCR4 on microglia to evoke interleukin-1β (IL-1β) release. Pharmacological studies determined that sequential activation of CXCR4, the IL-1β receptor, and the N-methyl-d-aspartate receptor was required. Expression of alternative reading frame polypeptide, which inhibits the ubiquitin ligase murine double minute 2, protected synapses, implicating the ubiquitin-proteasome pathway. Cannabimimetic drugs are of particular relevance to HAD because of their clinical and illicit use in patients with AIDS. The cannabinoid receptor full agonist [(R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate salt] (Win55,212-2) inhibited gp120-induced IL-1β production and synapse in a manner reversed by a cannabinoid type 2 receptor antagonist. In contrast, Win55,212-2 did not inhibit synapse loss elicited by exposure to the HIV-1 protein Tat. These results indicate that cannabinoids prevent the impairment of network function produced by gp120 and, thus, might have therapeutic potential in HAD.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA07304, DA11806, DA07234]; and the National Science Foundation [Grant IOS0814549].

  • A preliminary version of this report was presented in abstract form (Kim H and Thayer SA. Cannabinoids inhibit gp120-induced synapse loss. Soc Neurosci Abstr 35:727.19, 2009).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.071647.

  • ABBREVIATIONS:

    HAD
    HIV-associated dementia
    HAND
    HIV-associated neurocognitive disorders
    CB1
    cannabinoid type 1 receptor
    CB2
    cannabinoid type 2 receptor
    PSD
    postsynaptic density protein
    PSD95-GFP
    postsynaptic density protein 95 fused to green fluorescent protein
    ARF
    alternative reading frame polypeptide
    DMEM
    Dulbecco's modified Eagle's medium
    MK801
    dizocilpine
    Win55212-2
    [(R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate salt]
    AM630
    6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl(4-methoxyphenyl)methanone
    AMD3100
    1,1′-[1,4-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride
    TKP
    threonine-lysine-proline
    HHSS
    HEPES-buffered Hanks' salt solution
    qRT-PCR
    quantitative real-time polymerase chain reaction
    nNOS
    neuronal nitric-oxide synthase
    PCR
    polymerase chain reaction
    IL-1β
    interleukin-1β
    l-NAME
    NG-nitro-l-arginine methyl ester hydrochloride
    nutlin-3
    (±)-4-[4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one
    ELISA
    enzyme-linked immunosorbent assay
    NMDA
    N-methyl-d-aspartate
    PBS
    phosphate-buffered saline
    BSA
    bovine serum albumin
    GFP
    green fluorescent protein
    ANOVA
    analysis of variance
    PI
    propidium iodide
    gp120
    glycoprotein 120.

  • Received February 8, 2011.
  • Accepted June 13, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (3)
Molecular Pharmacology
Vol. 80, Issue 3
1 Sep 2011
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Research ArticleArticle

Activation of Cannabinoid Type 2 Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

Hee Jung Kim, Angela H. Shin and Stanley A. Thayer
Molecular Pharmacology September 1, 2011, 80 (3) 357-366; DOI: https://doi.org/10.1124/mol.111.071647

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Research ArticleArticle

Activation of Cannabinoid Type 2 Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

Hee Jung Kim, Angela H. Shin and Stanley A. Thayer
Molecular Pharmacology September 1, 2011, 80 (3) 357-366; DOI: https://doi.org/10.1124/mol.111.071647
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