Energy dependency of glucocorticoid exacerbation of gp120 neurotoxicity.
The HIV envelope glycoprotein, gp120, a well documented neurotoxin, may be involved in AIDS-related dementia complex. gp120 works through an NMDA receptor- and calcium-dependent mechanism to damage neurons. We have previously demonstrated that both natural and synthetic glucocorticoids (GCs) exacerbate gp120-induced neurotoxicity and calcium mobilization in hippocampal mixed cultures. GCs, steroid hormones secreted during stress, are now shown to work in conjunction with gp120 to decrease ATP levels and to work synergistically with gp120 to decrease the mitochondrial potential in hippocampal cultures. Furthermore, energy supplementation blocked the ability of GCs to worsen gp120's effects on neuronal survival and calcium mobilization. A GC-induced reduction in glucose transport in hippocampal neurons, as previously documented, may contribute to this energetic dependency. These results may have clinical significance, considering the common treatment of severe cases of Pneumocystis carinii pneumonia, typical of HIV infection, with large doses of synthetic GCs.
Department of Biological Sciences, Stanford University, California 94305, USA.
S M
SM
Brooke
S A
SA
Howard
R M
RM
Sapolsky
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003345:Corticosterone / Q000494:pharmacology*; D004357:Drug Synergism; D004734:Energy Metabolism / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000506:poisoning*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats / Q000196:embryology
D015699:HIV Envelope Protein gp120; D009498:Neurotoxins; D000255:Adenosine Triphosphate; D002118:Calcium; D003345:Corticosterone