AIDSWEEKLY Plus, Monday, 1 September 1997
Daniel J. DeNoon, Senior Editor
Glucocorticoids increased the nerve-cell toxicity of an HIV protein in laboratory studies, while estrogen decreased the effect.
If the results are the same in humans with AIDS, the findings will have far-reaching clinical implications.
"One of the most serious complications of HIV infection is the frequent cases of Pneumocystis carinii pneumonia [PCP], and the current treatment of choice for serious cases involves administration of megadoses of synthetic glucocorticoids (GCs) such as those used in [our] study," wrote Stanford University researchers S. Brooke and colleagues.
Brooke et al. reported their findings in the Proceedings of the National Academy of Sciences ("Endocrine Modulation of the Neurotoxicity of gp120: Implications for AIDS-Related Dementia Complex," PNAS, 1997;94:9457-62).
Some 20 percent of people with AIDS develop AIDS dementia complex (ADC), a wide range of neurologic and neuropsychologic impairments apparently related to pathologic changes in the cortical and subcortical regions of the brain. Both in vitro and in vivo studies show that HIV envelope glycoprotein gp120 damages neurons and glial cells. HIV gp120 neurotoxicity involves a complicated cascade of events that apparently causes the release of a hypothetical, excitatory amino acid that leads to overactivation of glutamate receptors and mobilization of dangerous amounts of calcium.
Steroids also stimulate worsening calcium-dependent neurodegenerative events, while estrogens decrease glutamate- induced calcium mobilization.
Putting these observations together, Brooke et al. explored the interactions of gp120, GCs, and estradiol (the most important naturally-occurring estrogen) in cultures of primary hippocampal and cortical tissues from fetal rats.
"We observe that gp120-induced calcium mobilization and neurotoxicity are exacerbated by glucocorticoids, the adrenal steroids secreted during stress," Brooke et al. found. "Conversely, we also observe that estradiol protects neurons from the deleterious actions of gp120, reducing toxicity and calcium mobilization."
If these findings hold true for humans, they would imply that HIV(+) men would have a higher rate or degree of ADC than HIV(+) women. Moreover, they would suggest that estrogen could be used to treat or prevent ADC. Brooke et al. noted that ongoing clinical trials are testing the ability of estrogen to protect against late-onset Alzheimer disease.
On a more negative note, the findings would also mean that the use of large doses of GCs to treat PCP could worsen or even cause ADC.
"Although the number of severe cases of P. carinii pneumonia is declining, best estimates are that thousands of individuals are still treated annually in this megadose range (e.g., 160 mg of methylprednisolone per day for seven days)," Brooke et al. observed. "The present findings suggest that ... exposure to elevated GC concentrations might have adverse consequences; this possibility remains to be tested in a clinical setting."
GC elevations in AIDS patients might also occur for other reasons. Brooke et al. noted that people with AIDS have a high incidence of depression; depressive individuals tend to have elevated GC concentrations. Also, a subset of AIDS patients develop mild hypercortisolism, possibly as a result of gp120 stimulation of the adrenocortical axis.
This work was supported by a Howard Hughes Grant for Undergraduate Research and the Adler Foundation and the National Institutes of Health Grant RO1 MH53814.
The corresponding author for this study is R. Sapolsky, Department of Biological Sciences, Stanford University, Stanford, California 94305. Email: sapolsky@leland.stanford.edu.
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