U50,488 protection against HIV-1-related neurotoxicity: Involvement of quinolinic acid suppression

Chun C. Chao, Shuxian Hu, Genya Gekker, James R. Lokensgard, Melvyn P. Heyes, Phillip K. Peterson

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The pathogenesis of human immunodeficiency virus type 1 (HIV-1) encephalopathy has been associated with multiple factors including the neurotoxin quinolinate (an endogenous N-methyl-D-aspartate [NMDA] receptor ligand) and viral proteins. The κ opioid receptor (KOR) agonist U50,488 recently has been shown to inhibit HIV-1 p24 antigen production in acutely infected microglial cell cultures. Using primary human brain cell cultures in the present study, we found that U50,488 also suppressed in a dose-dependent manner the neurotoxicity mediated by supernatants derived from HIV-1-infected microglia. This neuroprotective effect of U50,488 was blocked by the KOR selective antagonist nor-binaltorphimine. The neurotoxic activity of the supernatants from HIV-1-infected microglia was blocked by the NMDA receptor antagonists 2-amino-5-phosphonovalerate and MK-801. HIV-1 infection of microglial cell cultures induced the release of quinolinate, and U50,488 dose-dependently suppressed quinolinate release by infected microglial cell cultures with a corresponding inhibition of HIV-1 p24 antigen levels. These findings suggest that the kappa opioid ligand U50,488 may have therapeutic potential in HIV-1 encephalopathy by attenuating microglial cell production of the neurotoxin quinolinate and viral proteins. Copyright (C) 1999 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)150-160
Number of pages11
JournalNeuropharmacology
Volume39
Issue number1
DOIs
StatePublished - Jan 2000

Bibliographical note

Funding Information:
This study was supported in part by United Public Health Service grants DA09924, DA04381, and T32-DA07239 from the National Institute on Drug Abuse.

Keywords

  • HIV
  • N-methyl-D-aspartate receptor
  • Neurotoxicity
  • Opioids
  • Quinolinate

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