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Research ArticleArticle

Activation of CB2 Cannabinoid Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

Hee Jung Kim, Angela H Shin and Stanley A. Thayer
Molecular Pharmacology June 13, 2011, mol.111.071647; 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 CNS 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 GFP (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= 195±79 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 NMDA receptor was required. Expression of ARF, which inhibits the ubiquitin ligase MDM2, protected synapses, implicating the ubiquitin-proteasome pathway. Cannabimimetic drugs are of particular relevance to HAD because of their clinical and illicit use in AIDS patients. The cannabinoid receptor full agonist Win55,212-2 inhibited gp120-induced IL-1β production and PSD loss in a manner reversed by a CB2 receptor antagonist. In contrast, Win55,212-2 did not inhibit PSD 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.

  • Cannabinoid
  • Glutamate
  • Interleukins
  • Fluorescence techniques
  • Excitotoxicity, neurodegeneration
  • Synaptic plasticity
  • Received February 8, 2011.
  • Revision received June 10, 2011.
  • Accepted June 13, 2011.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 99 (3)
Molecular Pharmacology
Vol. 99, Issue 3
1 Mar 2021
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Research ArticleArticle

Activation of CB2 Cannabinoid Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

Hee Jung Kim, Angela H Shin and Stanley A. Thayer
Molecular Pharmacology June 13, 2011, mol.111.071647; DOI: https://doi.org/10.1124/mol.111.071647

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Research ArticleArticle

Activation of CB2 Cannabinoid Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

Hee Jung Kim, Angela H Shin and Stanley A. Thayer
Molecular Pharmacology June 13, 2011, mol.111.071647; DOI: https://doi.org/10.1124/mol.111.071647
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