Much research supports the notion that the dementia complex associated with AIDS infection (ADC), is caused by the HIV-1 virus invading the brain macrophages, astrocytes, and microglia triggering various mediators involving contributing cell types setting up a series of cytokine-mediate events leading to the production of toxins which cause neuronal damage. (The HIV-1 envelope protein, glycoprotein 120 (gp120), will set up the same neurotoxic processes.) Many of the cytokine-mediated processes appear to involve signal transduction events which have antioxidant-sensitive steps and cause the induction of various genes, including TGF-alpha and inducible (iNOS). (iNOS mediates the production of large levels of nitric oxide [NO] and either it or one of its metabolites [e.g., peroxynitrite] is toxic to most neurons.) The Principal Investigator and his coworkers have obtained novel and striking preliminary data that may be useful in understanding neuronal damage and offer leads to possibly treat AIDS dementia. They have found, utilizing a direct NO trapping technique in a rat neonate model where gp120 administration causes delayed neuronal development, that high levels of NO are trapped in the brain and that a neuroprotective compound, PBN, not only prevents the NO build-up but prevents the gp120-mediated slowdown in neuronal development. In brain cell culture, gp120 plus various cytokines induce iNOS gene expression and the formation of large amounts of NO. This is prevented by PBN. The long-range goal of the proposed research is to define the role that NO plays in neurological damage, examine the role of escalating cytokine-mediated iNOS gene induction and of oxidative events, and ascertain the neuroprotective mechanism of action of PBN and related compounds in experimental models of ADC. In addition, the results obtained in ADC models will be compared to those obtained from the analysis of CSF of AIDS patients with the view that the knowledge obtained will be valuable in the development of potential therapeutic approaches to the treatment of ADC.
The specific aims are: (1) first, to ascertain the role of NO and oxidative damage and the mediating effect that specific cytokines play in neurotoxicity associate with ADC, utilizing rat brain cell culture and rat neonate models and, second, to ascertain the role of iNOS and the gene expression of specific cytokines in neurotoxic processes using PBN and several related compounds and to ascertain the neuroprotective action of these compounds; (2) to develop a mouse transgenic model wherein gp120 expression in astrocytes can be turned """"""""on"""""""" or """"""""off"""""""" at any specific time in the animal's life and conduct studies to ascertain the role that iNOS and specific cytokine gene expression plays in neurologic damage; and (3) to ascertain whether NO oxidation products (NO2-, NO3-), as well as oxidized protein and specific cytokines, are altered in the CSF of AIDS patients in reference to their degree of dementia and their staging in terms of disease progression.
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