Gonadal steroids differentially modulate neurotoxicity of HIV and cocaine: testosterone and ICI 182,780 sensitive mechanism.
BACKGROUND
HIV Associated Dementia (HAD) is a common complication of human immunodeficiency virus (HIV) infection that erodes the quality of life for patients and burdens health care providers. Intravenous drug use is a major route of HIV transmission, and drug use is associated with increased HAD. Specific proteins released as a consequence of HIV infection (e.g., gp120, the HIV envelope protein and Tat, the nuclear transactivating protein) have been implicated in the pathogenesis of HAD. In primary cultures of human fetal brain tissue, subtoxic doses of gp120 and Tat are capable of interacting with a physiologically relevant dose of cocaine, to produce a significant synergistic neurotoxicity. Using this model system, the neuroprotective potential of gonadal steroids was investigated.


RESULTS
17beta-Estradiol (17beta-E2), but not 17alpha-estradiol (17alpha-E2), was protective against this combined neurotoxicity. Progesterone (PROG) afforded limited neuroprotection, as did dihydrotestosterone (DHT). The efficacy of 5alpha-testosterone (T)-mediated neuroprotection was robust, similar to that provided by 17beta-E2. In the presence of the specific estrogen receptor (ER) antagonist, ICI-182,780, T's neuroprotection was completely blocked. Thus, T acts through the ER to provide neuroprotection against HIV proteins and cocaine. Interestingly, cholesterol also demonstrated concentration-dependent neuroprotection, possibly attributable to cholesterol's serving as a steroid hormone precursor in neurons.


CONCLUSIONS
Collectively, the present data indicate that cocaine has a robust interaction with the HIV proteins gp120 and Tat that produces severe neurotoxicity, and this toxicity can be blocked through pretreatment with ER agonists.
Kendall
Sherie L
SL
Department of Behavioral Sciences, University of Kentucky, Lexington, Kentucky, USA. skend2@uky.edu
Anderson
Caroline F
CF
Nath
Avindra
A
Turchan-Cholewo
Jadwiga
J
Land
Cantey L
CL
Mactutus
Charles F
CF
Booze
Rosemarie M
RM
D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D003042:Cocaine / Q000633:toxicity*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005333:Fetus; D000077267:Fulvestrant; D015696:Gene Products, tat / Q000633:toxicity*; D012739:Gonadal Steroid Hormones / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology; D013739:Testosterone / Q000494:pharmacology*
D015696:Gene Products, tat; D012739:Gonadal Steroid Hormones; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D000077267:Fulvestrant; D013739:Testosterone; D004958:Estradiol; D003042:Cocaine