17beta-estradiol reduces neuronal apoptosis induced by HIV-1 gp120 in the neocortex of rat.
The human immunodeficiency virus type 1 (HIV-1) coat glycoprotein gp120 represents a likely contributor to the development of HIV-1 associated dementia (HAD), a neurological syndrome often observed in AIDS patients and characterised by significant neuronal loss in the neocortex. Since recent studies have highlighted that female sex hormones represent potential neuroprotective agents against damage produced by acute and chronic injuries in the adult brain, we have investigated whether estrogens exert protection in a rat model of gp120 neurotoxicity. Our results demonstrate that systemic administration of 17beta-estradiol (E2, 0.02-0.2 mg/kg) significantly reduces apoptotic cell death observed in the neocortex of rat following subchronic i.c.v. administration of gp120 (100 ng/rat/day). Furthermore, both tamoxifen and ICI182,780, two selective antagonists of estrogen receptors (ER) in the brain, reverted the neuroprotective effect of E2. The molecular mechanism of estrogenic neuroprotection does not appear to involve modulation of the antiapoptotic Bcl-2 or the proapoptotic Bax since we failed to observe changes in the levels of the two proteins in the neocortical tissue after gp120 and/or E2 treatment. However, we detected increased levels of IL-1beta in the neocortex of rats injected with gp120, as early as 6h after drug administration, and this effect was potentiated following pretreatment with E2. Taken together, our results demonstrate that E2 exerts neuroprotection against gp120 neurotoxicity in vivo through a mechanism involving ER activation and, possibly, via modulation of neocortical levels of IL-1beta.
Corasaniti
M T
MT
Department of Pharmacobiological Science, University Magna Graecia, 88100 Catanzaro, Italy. mtcorasa@unicz.it
Amantea
D
D
Russo
R
R
Piccirilli
S
S
Leta
A
A
Corazzari
M
M
Nappi
G
G
Bagetta
G
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D019579:Neocortex / Q000166:cytology* / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D015699:HIV Envelope Protein gp120; D007375:Interleukin-1; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D004958:Estradiol