U50,488 protection against HIV-1-related neurotoxicity: involvement of quinolinic acid suppression.
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 kappa 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.
Chao
C C
CC
Institute for Brain and Immune Disorders, Minneapolis Medical Research Foundation and the University of Minnesota Medical School, USA.
Hu
S
S
Gekker
G
G
Lokensgard
J R
JR
Heyes
M P
MP
Peterson
P K
PK
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D015526:AIDS Dementia Complex; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects / Q000821:virology; D005333:Fetus; D016655:HIV Core Protein p24 / Q000032:analysis; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000821:virology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors
D016655:HIV Core Protein p24; D009292:Narcotic Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D017378:Quinolinic Acid