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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH053814-02
Application #
2416097
Study Section
AIDS and Related Research Study Section 7 (ARRG)
Project Start
1996-08-01
Project End
1999-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Munhoz, Carolina Demarchi; Sorrells, Shawn F; Caso, Javier R et al. (2010) Glucocorticoids exacerbate lipopolysaccharide-induced signaling in the frontal cortex and hippocampus in a dose-dependent manner. J Neurosci 30:13690-8
Zemlyak, Ilona; Brooke, Sheila; Sapolsky, Robert (2005) Estrogenic protection against gp120 neurotoxicity: role of microglia. Brain Res 1046:130-6
Dinkel, Klaus; Dhabhar, Firdaus S; Sapolsky, Robert M (2004) Neurotoxic effects of polymorphonuclear granulocytes on hippocampal primary cultures. Proc Natl Acad Sci U S A 101:331-6
Brooke, Sheila M; Sapolsky, Robert M (2003) Effects of glucocorticoids in the gp120-induced inhibition of glutamate uptake in hippocampal cultures. Brain Res 972:137-41
Lim, Min Chin; Brooke, Sheila M; Sapolsky, Robert M (2003) gp120 neurotoxicity fails to induce heat shock defenses, while the over expression of hsp70 protects against gp120. Brain Res Bull 61:183-8
Dinkel, Klaus; MacPherson, Anna; Sapolsky, Robert M (2003) Novel glucocorticoid effects on acute inflammation in the CNS. J Neurochem 84:705-16
Dinkel, Klaus; Ogle, William O; Sapolsky, Robert M (2002) Glucocorticoids and central nervous system inflammation. J Neurovirol 8:513-28
Zemlyak, Ilona; Brooke, Sheila M; Sapolsky, Robert M (2002) Protection against gp120-induced neurotoxicity by an array of estrogenic steroids. Brain Res 958:272-6
Brooke, Sheila M; Sapolsky, Robert M (2002) Glucocorticoid exacerbation of gp120 neurotoxicity: role of microglia. Exp Neurol 177:151-8
Patel, Ravi; McIntosh, Laura; McLaughlin, John et al. (2002) Disruptive effects of glucocorticoids on glutathione peroxidase biochemistry in hippocampal cultures. J Neurochem 82:118-25

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