The neurological manifestations of AIDS affect approximately half of the children infected with HIV-1 and perhaps one-third of the adults. Many children with AIDS display delayed milestones and even frank cognitive and motor decline, causing substantial developmental disabilities and mental retardation. Quite apart from superinfections with opportunistic organisms and malignancy, damage in the CNS in AIDS appears to be most closely associated with toxins released by brain macrophages after they have been infected by HIV-1 or stimulated by its coat protein, gpl20. Neurons are injured in this process, and at least part of their damage is accounted for by the macrophage toxic factors leading to overexcitation of glutamate receptors, especially of the N-methyl-D- aspartate (NMDA) subtype. Therefore, in Project III our group of investigators studies the effects of clinically-tolerated NMDA antagonists in preventing the neuronal injury engendered by gp120 (or a fragment of gpl20). In published experiments, our laboratory has shown that NMDA antagonists can effectively prevent gpl20-induced neuronal injury in vitro in mixed neuronal/glial cultures. Subsequently, this work has been corroborated by several other laboratories. In the proposed studies, we will draw on the results of Projects I and II to use the clinically-tolerated NMDA antagonists developed in those studies. We will use these NMDA antagonists to prevent gpl20-mediated neurotoxicity, first in vitro and then in vivo, using both recombinant and purified gpl20 injections into rat pups as well as a transgenic- gp120 mouse model.
The Specific Aims of Project III are as follows: 1. To test the clinically-tolerated NMDA antagonists memantine (and related adamantanes) and redox-related forms of nitric oxide in vitro and in vivo for their ability to ameliorate HIV-l coat protein (gpl20) toxicity in-- (a) rat and human primary central neuronal/glial cultures incubated with gpl20, and in (b) rat pups in vivo injected with picomole quantities of gpl20, which in preliminary studies produce striking lesions in the cortex, and in (c) mice in vivo containing a gpl20 transgene that has been demonstrated to be associated with neuronal damage. 2. To test the potential contribution of neuronal nitric oxide to the CNS damage in the gpl20-transgenic mice. To do this we will analyze by histology, by magnetic resonance imaging and spectroscopy (MRI/MRS), and by electron parmagnetic resonance (EPR) spectroscopy the offspring of GFAP-gpl20 transgenic mice crossed with neuronal nitric oxide synthase (NOS) knockout mice. It is anticipated that these preclinical studies investigating the role of the NMDA receptor and its downstream activation of NOS may lead to new treatments of the neurological manifestations of AIDS.
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