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 expe rience a dementia characterized by mental slowing and memory loss. Motor dy sfunction may also accompany this condition. The pathogenesis of the dement ia is not known, but microscopic examination of brain tissue from those aff licted shows evidence of chronic inflammation, reactive gliosis and cell de ath. Neurotoxic factors produced from activated macrophage or microglial ce lls such as tumor necrosis factor-alpha (TNF alpha), gp120 and quinolinic a cid have been implicated as agents for the cell death which often appears t o occur by an apoptotic mechanism. CPI-1189, a drug currently undergoing cl inical evaluation as a treatment for the dementia associated with AIDS, is shown in this paper to mitigate apoptosis induced by TNF alpha, gp120, and necrosis induced by quinolinic acid. In addition, CPI-1189 mitigates the ce ll death produced by supernatants from cultured macrophages obtained from p atients with AIDS dementia. The exact mechanism by which CPI-1189 prevents neurotoxicity is not known; however, protection from TNF alpha and supernat ant-induced toxicity does not appear to involve NF kappaB translocation, an d appears to be associated with an increase in activated ERK-MAP kinase. Th ese findings may have implications for other neurological diseases where ap optotic cell death contributes to neurodegeneration. (C) 2001 Elsevier Scie nce B.V. All rights reserved.