CPI-1189 attenuates effects of suspected neurotoxins associated with AIDS dementia: a possible role for ERK activation.
Individuals infected with the human immunodeficiency virus (HIV) often experience a dementia characterized by mental slowing and memory loss. Motor dysfunction may also accompany this condition. The pathogenesis of the dementia is not known, but microscopic examination of brain tissue from those afflicted shows evidence of chronic inflammation, reactive gliosis and cell death. Neurotoxic factors produced from activated macrophage or microglial cells such as tumor necrosis factor-alpha (TNFalpha), gp120 and quinolinic acid have been implicated as agents for the cell death which often appears to occur by an apoptotic mechanism. CPI-1189, a drug currently undergoing clinical evaluation as a treatment for the dementia associated with AIDS, is shown in this paper to mitigate apoptosis induced by TNFalpha, gp120, and necrosis induced by quinolinic acid. In addition, CPI-1189 mitigates the cell death produced by supernatants from cultured macrophages obtained from patients with AIDS dementia. The exact mechanism by which CPI-1189 prevents neurotoxicity is not known; however, protection from TNFalpha and supernatant-induced toxicity does not appear to involve NFkappaB translocation, and appears to be associated with an increase in activated ERK-MAP kinase. These findings may have implications for other neurological diseases where apoptotic cell death contributes to neurodegeneration.
Pulliam
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L
Departments of Laboratory Medicine and Medicine, University of California, San Francisco, CA 94143, USA. lynnp@itsa.ucsf.edu
Irwin
I
I
Kusdra
L
L
Rempel
H
H
Flitter
W D
WD
Garland
W A
WA
D015526:AIDS Dementia Complex / Q000209:etiology / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002073:Butanes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000821:virology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D009589:Nitrogen Oxides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D017378:Quinolinic Acid / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D002073:Butanes; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D005419:Flavonoids; D015699:HIV Envelope Protein gp120; D016328:NF-kappa B; D009498:Neurotoxins; D009589:Nitrogen Oxides; D014409:Tumor Necrosis Factor-alpha; C406025:CPI 1189; D020928:Mitogen-Activated Protein Kinases; D017378:Quinolinic Acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one