Glucocorticoid modulation of gp120-induced effects on calcium-dependent degenerative events in primary hippocampal and cortical cultures.
The HIV coat protein gp120 has been implicated in damaging the nervous system and may play a role in AIDS-related dementia complex. The glycoprotein triggers the release of a glutamatergic agent from infected microglia and macrophages, causing NMDA receptor- and calcium-dependent excitotoxic damage to neurons. We have previously shown that glucocorticoids, the adrenal steroids secreted during stress, worsen gp120 neurotoxicity and calcium mobilization in various brain regions. This study explores events down-stream of gp120-induced calcium mobilization, specifically, generation of reactive oxygen species (ROS) and subsequent lipid peroxidation, destruction of the cytoskeleton through spectrin proteolysis, and the glucocorticoid modulation of these events in primary hippocampal cultures. We observe that 200 pM gp120 causes a significant accumulation of ROS, including superoxide, and of lipid peroxidation. Counter to our predictions, pretreatment with the glucocorticoid corticosterone (CORT) did not worsen the effects of gp120 on ROS accumulation, but did increase lipid peroxidation. We also observed that neither gp120 alone nor gp120 plus CORT caused detectable proteolysis of the cytoskeletal protein spectrin, whose breakdown has been shown to be a damaging consequence of calcium excess in other models of necrotic neuronal injury.
Howard
S A
SA
Department of Biological Sciences, Stanford University, California 94305, USA.
Nakayama
A Y
AY
Brooke
S M
SM
Sapolsky
R M
RM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D018929:Cell Culture Techniques; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D003345:Corticosterone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D017628:Microglia / Q000187:drug effects; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
D005938:Glucocorticoids; D015699:HIV Envelope Protein gp120; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D013481:Superoxides; D010447:Peptide Hydrolases; D002118:Calcium; D003345:Corticosterone