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      Estrogen protects against the synergistic toxicity by HIV proteins, methamphetamine and cocaine

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          Abstract

          Background

          Human immunodeficiency virus (HIV) infection continues to increase at alarming rates in drug abusers, especially in women. Drugs of abuse can cause long-lasting damage to the brain and HIV infection frequently leads to a dementing illness.To determine how these drugs interact with HIV to cause CNS damage, we used an in vitro human neuronal culture characterized for the presence of dopaminergic receptors, transporters and estrogen receptors. We determined the combined effects of dopaminergic drugs, methamphetamine, or cocaine with neurotoxic HIV proteins, gp120 and Tat.

          Results

          Acute exposure to these substances resulted in synergistic neurotoxic responses as measured by changes in mitochondrial membrane potential and neuronal cell death. Neurotoxicity occurred in a sub-population of neurons. Importantly, the presence of 17beta-estradiol prevented these synergistic neurotoxicities and the neuroprotective effects were partly mediated by estrogen receptors.

          Conclusion

          Our observations suggest that methamphetamine and cocaine may affect the course of HIV dementia, and additionally suggest that estrogens modify the HIV-drug interactions.

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          Most cited references32

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          Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta.

          G G Kuiper, B. Carlsson, K Grandien … (1997)
          The rat estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand binding domain and in the N-terminal transactivation domain. In this study we investigated the messenger RNA expression of both ER subtypes in rat tissues by RT-PCR and compared the ligand binding specificity of the ER subtypes. Saturation ligand binding analysis of in vitro synthesized human ER alpha and rat ER beta protein revealed a single binding component for 16 alpha-iodo-17 beta-estradiol with high affinity [dissociation constant (Kd) = 0.1 nM for ER alpha protein and 0.4 nM for ER beta protein]. Most estrogenic substances or estrogenic antagonists compete with 16 alpha-[125I]iodo-17 beta-estradiol for binding to both ER subtypes in a very similar preference and degree; that is, diethylstilbestrol > hexestrol > dienestrol > 4-OH-tamoxifen > 17 beta-estradiol > coumestrol, ICI-164384 > estrone, 17 alpha-estradiol > nafoxidine, moxestrol > clomifene > estriol, 4-OH-estradiol > tamoxifen, 2-OH-estradiol, 5-androstene-3 beta, 17 beta-diol, genistein for the ER alpha protein and dienestrol > 4-OH-tamoxifen > diethylstilbestrol > hexestrol > coumestrol, ICI-164384 > 17 beta-estradiol > estrone, genistein > estriol > nafoxidine, 5-androstene-3 beta, 17 beta-diol > 17 alpha-estradiol, clomifene, 2-OH-estradiol > 4-OH-estradiol, tamoxifen, moxestrol for the ER beta protein. The rat tissue distribution and/or the relative level of ER alpha and ER beta expression seems to be quite different, i.e. moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ER alpha and prostate, ovary, lung, bladder, brain, uterus, and testis for ER beta. The described differences between the ER subtypes in relative ligand binding affinity and tissue distribution could contribute to the selective action of ER agonists and antagonists in different tissues.
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            Striatal dopamine nerve terminal markers in human, chronic methamphetamine users.

            Neil R. Anthony, S Kish, J Haycock … (1996)
            Methamphetamine is a drug that is significantly abused worldwide, Although long-lasting depletion of dopamine and other dopamine nerve terminal markers has been reported in striatum of nonhuman primates receiving very high doses of the psychostimulant, no information is available for humans. We found reduced levels of three dopamine nerve terminal markers (dopamine, tyrosine hydroxylase and the dopamine transporter) in post-mortem striatum (nucleus accumbens, caudate, putamen) of chronic methamphetamine users. However, levels of DOPA decarboxylase and the vesicular monoamine transporter, known to be reduced in Parkinson's disease, were normal. This suggests that chronic exposure to methamphetamine does not cause permanent degeneration of striatal dopamine nerve terminals at the doses used by the young subjects in our study. However, the dopamine reduction might explain some of the dysphoric effects of the drug, whereas the decreased dopamine transporter could provide the basis for dose escalation occurring in some methamphetamine users.
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              Sex differences in HIV-1 viral load and progression to AIDS.

              Jordan Vlahov, Joseph Margolick, J Astemborski … (1998)
              Plasma HIV-1 RNA measurements are used for initiation of antiretroviral treatments. Whether the viral-load association with prognosis is similar in women and men is unknown. We studied 812 specimens from 650 injection-drug users (IDUs) participating in a continuous observational study of patients based in a community clinic. HIV-1 load was measured by branched-chain DNA on samples from 527 IDUs from the baseline visit, and by reverse-transcriptase PCR and quantitative microculture on samples from 285 IDUs at a follow-up visit 3 years later. FNDINGS: Women had lower median viral-load measurements than men by branched-chain DNA (3365 vs 8907 copies/mL; p=0.001), reverse-transcriptase PCR (45416 vs 93130 copies/mL; p=0.02), and quantitative microculture (5 vs 8 infectious units per million peripheral blood mononuclear cells; p=0.015). This association remained even after adjustment for CD4 cell count, race, and drug use within the previous 6 months. Time to AIDS was statistically similar for men and women in a univariate proportional-hazards model and in a model adjusting for CD4 cell count. Proportional-hazards models showed that women with the same viral load as men had a 1.6-fold higher risk of AIDS (95% CI 1.10-2.32); or, equivalently, that women with half the viral load of men had a similar time to AIDS as men. Although a biological mechanism remains unclear, these data suggest that current recommendations for HIV-1 viral-load thresholds to initiate antiretroviral therapy should be revised downwards for women.
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                Author and article information

                Journal
                Journal ID (nlm-ta): BMC Neurosci
                Title: BMC Neuroscience
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1471-2202
                Publication date Collection: 2001
                Publication date (Electronic): 2 March 2001
                Volume: 2
                Page: 3
                Affiliations
                [1 ]Department of Neurology, University of Kentucky, Lexington KYl, USA
                [2 ]Department of Microbiology and Immunology, University of Kentucky, Lexington KYl, USA
                [3 ]Department of Anatomy and Neurobiology, University of Kentucky, Lexington KYl, USA
                [4 ]Department of Physiology, University of Kentucky, Lexington KY, USA
                [5 ]Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD, USA
                Article
                Publisher ID: 1471-2202-2-3
                DOI: 10.1186/1471-2202-2-3
                PMC ID: 29103
                PubMed ID: 11252157
                SO-VID: 3e557023-f09f-4016-9238-d27ab0dbd840
                Copyright © Copyright © 2001 Turchan et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
                History
                Date received : 24 January 2001
                Date accepted : 2 March 2001
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Neurosciences
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                ScienceOpen disciplines: Neurosciences

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