The unifying theme of the competing renewal of this Program Project is a cellular and molecular approach to developmental neurology in an attempt to uncover processes leading to neonatal brain injury and mental retardation. Three inter-related projects are planned. They all concern the influence of overstimulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and its role in neuronal damage during hypoxic-ischemic brain injury and during the loss of developmental milestones associated with AIDS dementia. For many years, hypoxic- ischemic insults have been known to result in mental retardation and developmental delay. Only in recent years, however, has it become apparent that AIDS is associated with an approximately 50% incidence in delayed milestones and frank cognitive decline in children infected with HIV-1. This Program Project Group of Investigators and others have shown that at least part of this damage to the nervous system appears to be mediated by excessive NMDA receptor activation that is not adequately treated by currently available therapeutic regimens. This grant plans to study the underlying molecular mechanisms that can be used to down- regulate NMDA receptor activity in a clinically-tolerated manner using a combination of techniques ranging from molecular biology to patch- clamp recording (Project I). In this manner two types of clinically- tolerated NMDA antagonists are being developed: (1)open-channel blockers of the memantine class of compounds, and (2) redox agents related to nitric oxide, including the well-known clinically-tolerated drug nitroglycerin (NTG). In addition, novel agents including new members of the memantine family will be tested as well as a combination drug, which has features of both an NMDA open-channel blocker and a redox agent. In Project II, these novel, clinically-tolerated NMDA antagonists will be tested in animal models of hypoxic-ischemic brain injury. In Project III, these same NMDA antagonists will be tested vitro and in animal models of AIDS dementia. These models consist of stereotactic injections of gpl20 (or control peptides) and a gp120-transgenic mouse. An important feature of this Program Project is its multi-disciplinary approach using molecular, neurophysiologic, pharmacologic, and morphologic techniques in both cell culture and whole-animal experiments. A proposed Neuroscience Core Unit would provide a central tissue culture facility with equipment and supplies common to all of the projects. In addition, this Core will provide state-of-the-art magnetic resonance (MR) and electron paramagnetic resonance (EPR) imaging and/or spectroscopy expertise and facilities to allow the development of surrogate markers of neuronal damage in hypoxic-ischemic insults and in the neurological manifestations of AIDS in neonates and children. In the future, such surrogate markers will be useful in quantifying the beneficial affects of potential therapies when these drugs are applied in the clinic.
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