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 17β-Estradiol (17β-$ E_{2} $), but not 17α-estradiol (17α-$ E_{2} $), was protective against this combined neurotoxicity. Progesterone (PROG) afforded limited neuroprotection, as did dihydrotestosterone (DHT). The efficacy of 5α-testosterone (T)-mediated neuroprotection was robust, similar to that provided by 17β-$ E_{2.} $ 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. Conclusion 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..

Medienart:

E-Artikel

Erscheinungsjahr:

2005

Erschienen:

2005

Enthalten in:

Zur Gesamtaufnahme - volume:6

Enthalten in:

BMC neuroscience - 6(2005), 1 vom: 08. Juni

Sprache:

Englisch

Beteiligte Personen:

Kendall, Sherie L [VerfasserIn]
Anderson, Caroline F [VerfasserIn]
Nath, Avindra [VerfasserIn]
Turchan-Cholewo, Jadwiga [VerfasserIn]
Land, Cantey L [VerfasserIn]
Mactutus, Charles F [VerfasserIn]
Booze, Rosemarie M [VerfasserIn]

Links:

Volltext [kostenfrei]

Themen:

Androgen Receptor
Cocaine
Gonadal Steroid
Human Immunodeficiency Virus
Human Immunodeficiency Virus Infection

Anmerkungen:

© Kendall et al; licensee BioMed Central Ltd. 2005. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (

doi:

10.1186/1471-2202-6-40

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC2101201003

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