Benzodiazepines, glia, and HIV-1 neuropathogenesis.
Although the precise mechanisms whereby HIV-1 infection induces neurodegeneration have yet to be determined, a great deal of evidence has incriminated glial cells and the production of proinflammatory mediators in this pathologic process. For this reason, ideal therapeutic agents for the treatment of AIDS dementia would attenuate HIV-1 neuropathogenesis through both direct inhibition of viral expression and suppression of brain cell-produced immune mediators. Benzodiazepines (BDZs), such as Valium, are extensively prescribed drugs for anxiety disorders, which readily cross the blood-brain barrier and have demonstrated immunomodulatory properties. BDZs bind to primary human microglial cells, the principal site of HIV-1 replication in the brain, and inhibit lipopolysaccharide (LPS) induced tumour necrosis factor (TNF-alpha) production by these cells in a concentration-dependent manner. Treatment of HIV-1-infected primary human microglial, as well as mixed glial/neuronal, cell cultures with BDZs inhibits the expression of HIV-1 p24 antigen. BDZ-induced inhibition of HIV-1 expression in chronically infected promonocytic (U1) cells has been found to be associated with decreased activation of the nuclear transcription factor kappa B (NF-kappa B). Because HIV-1 expression is critically dependent on the cellular transcription machinery, inhibition of the activation of transcription factors, which participate in both HIV-1 expression and the production of neurotoxic immune mediators, by BDZ analogs may provide new therapeutic options for AIDS dementia.
Lokensgard
J R
JR
Institute for Brain and Immune Disorders, Minneapolis Medical Research Foundation, MN, USA.
Chao
C C
CC
Gekker
G
G
Hu
S
S
Peterson
P K
PK
D015526:AIDS Dementia Complex / Q000188:drug therapy / Q000503:physiopathology / Q000821:virology*; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002998:Clonazepam / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D015195:Drug Design; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016655:HIV Core Protein p24 / Q000096:biosynthesis / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D016328:NF-kappa B / Q000378:metabolism; D009410:Nerve Degeneration; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D016655:HIV Core Protein p24; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D001569:Benzodiazepines; D002998:Clonazepam; D003975:Diazepam