It is now believed that the neurobehavioral and neuropathologic indices of AIDS Dementia Complex can arise directly from HIV infection of the brain. Specifically, HIV infection of macrophages and microglia is thought to lead to the release of a neuroendangering factor(s). Attention has focused on the role of the HIV glycoprotein gp120 in this picture; gp120 can damage cultured neurons via indirect activation of a cascade involving glutamatergic synapses, the NMDA receptor and cytosolic calcium mobilization. Furthermore, our work indicate that gp120 can suppress metabolism in neuronal cultures, a notable finding given that the neuropathology of HIV infection appears to be far more about neuronal dysfunction than about neuron death. The proposed studies test the hypothesis that glucocorticoids (GCs), the adrenal steroids released during stress, can worsen the deleterious effects of gp120 in the rat brain. GCs can damage neurons in the hippocampus and impair the capacity of hippocampal, cortical and striatal neurons to survive necrotic insults. This GC-induced endangerment is energetic in nature, probably arising from GCs inhibition of glucose uptake in the brain. As a result, neurons are less capable of the costly tasks of controlling the waves of potentially lethal glutamate and calcium loosened during necrotic insults, thereby exacerbating damage. In testing whether GCs augment the damaging effects of gp120, we will determine a) whether GCs increase gp120-induced calcium mobilization; b) if gp120 causes calcium-dependent cytoskeletal proteolysis and oxidative damaged and, if so, if this is worsened by GCs; c) if GCs exacerbate the suppressive effects of gp120 on metabolism or gp120-induced declines in ATP and phosphocreatine content; e) if GCs increase the toxicity of gp120. Studies will be carried out in tissue slices from cortex, striatum and hippocampus, and from cortical, striatal and hippocampal primary cultures. The effects of both endogenous and synthetic GCs will be tested, as well as of stress itself (in rats from whom slices are generated). We will also test whether any GC effects are reversible with energy supplementation, as with other instances of GC neuroendangerment. GCs are administered in megadose quantities to control the Pneumocystis carinii pneumonia of HIV infection; it seems essential to determine the neurobehavioral and neuropathologic consequences of this. That, coupled with the possible implications of the stressfulness of HIV infection prompt the proposed studies.
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