The neurological manifestations of AIDS affect approximately half of the children infected with HIV-1 and perhaps on-quarter to one-third of adults. Many children with AIDS display delayed milestones and even frank cognitive and motor decline, causing substantial development disabilities and mental retardation. Quite apart from super-infections with opportunistic organisms and malignancy, at least some degree 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, gp120. Neurons are injured in this process and may undergo apoptosis, and at least part of their damage is accounted for by the macrophage and possibly astrocyte toxic factors leading to over-excitation of glutamate receptors, especially of the N-methyl-D-aspartate. (NMDA) subtype. Therefore, in Project, our group of investigators studies the effects of clinically-tolerated NMDA antagonists in preventing the neuronal injury engendered by gp120 in the following model systems: (a) in vitro in rodent cerebrocortical cultures, (b) in vivo in a rodent retinal model using intravitreal injection of gp120, (c) in vivo in a gp120- transgenic mouse model, and (d) in vivo in a SCID (subacute combined immunodeficiency) mouse model of AIDS dementia produced by intracerebral injection of HIV-infected human monocytes. Here we propose to use the clinically-tolerated NMDA antagonists developed in Projects. We will also study apoptotic signaling pathways that may be present in AIDS brains, including those mediated by nitric oxide and caspases (similar to pathways triggered by NMDA and hypoxia-ischemia in Project). To accomplish these goals, transgenic and knockout mice that disrupt these signaling pathways will be used for the intravitreal injection of gp120 or will be crossed with gp120-transgenic mice. The resulting gp120-injected or bigenic mice will be analyzed histologically by confocal laser scanning microscopy and by magnetic resonance spectroscopy (MRS) in the Program's CORE facilities to determine if disruption of these signalling pathways ameliorates gp120-induced damage. It is anticipated that these preclinical studies investigating the role of the NMDA receptor and it signaling pathways to neuronal cell injury may lead to new treatment of the neurological manifestations of AIDS. In the previous grant period, this has already been realized to some extent with one of the NMDA receptor antagonist developed by this Program Project (memantine) going into a nation-wide clinical trial for AIDS dementia.
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