| Description: |
17Alpha-estradiol is a potent estrogen and carcinogen during development. 17Alpha-estradiol has neuroprotective activity, it is effective in lowering cerebral amyloid-beta levels in AbetaPPSWE transgenic mice, it may help to develop safe and effective therapeutics to treat Alzheimer disease. 17Alpha-estradiol induces aromatase activity in isolated human hair follicles, it may be used for topical treatment of androgenetic alopecia (AGA) in women. 17Alpha-estradiol also arrests cell cycle progression at G2/M and induces apoptotic cell death in human acute leukemia Jurkat T cells. |
| Targets: |
Beta Amyloid | Bcl-2/Bax | Caspase | PARP | Estrogen receptor | GABA Receptor | Progestogen receptor |
| In vitro: |
| Toxicol Appl Pharmacol. 2008 Sep 15;231(3):401-12. | | 17Alpha-estradiol arrests cell cycle progression at G2/M and induces apoptotic cell death in human acute leukemia Jurkat T cells.[Pubmed: 18603276] |
METHODS AND RESULTS:
A pharmacological dose (2.5-10 microM) of 17alpha-Estradiol (17alpha-E(2)) exerted a cytotoxic effect on human leukemias Jurkat T and U937 cells, which was not suppressed by the estrogen receptor (ER) antagonist ICI 182,780. Along with cytotoxicity in Jurkat T cells, several apoptotic events including mitochondrial cytochrome c release, activation of caspase-9, -3, and -8, PARP degradation, and DNA fragmentation were induced. The cytotoxicity of 17alpha-E(2) was not blocked by the anti-Fas neutralizing antibody ZB-4. While undergoing apoptosis, there was a remarkable accumulation of G(2)/M cells with the upregulatoin of cdc2 kinase activity, which was reflected in the Thr56 phosphorylation of Bcl-2. Dephosphorylation at Tyr15 and phosphorylation at Thr161 of cdc2, and significant increase in the cyclin B1 level were underlying factors for the cdc2 kinase activation. Whereas the 17alpha-E(2)-induced apoptosis was completely abrogated by overexpression of Bcl-2 or by pretreatment with the pan-caspase inhibitor z-VAD-fmk, the accumulation of G(2)/M cells significantly increased. The caspase-8 inhibitor z-IETD-fmk failed to influence 17alpha-E(2)-mediated caspase-9 activation, but it markedly reduced caspase-3 activation and PARP degradation with the suppression of apoptosis, indicating the contribution of caspase-8; not as an upstream event of the mitochondrial cytochrome c release, but to caspase-3 activation. In the presence of hydroxyurea, which blocked the cell cycle progression at the G(1)/S boundary, 17alpha-E(2) failed to induce the G(2)/M arrest as well as apoptosis.
CONCLUSIONS:
These results demonstrate that the cytotoxicity of 17alpha-E(2) toward Jurkat T cells is attributable to apoptosis mainly induced in G(2)/M-arrested cells, in an ER-independent manner, via a mitochondria-dependent caspase pathway regulated by Bcl-2. | | Exp Dermatol. 2002 Aug;11(4):376-80. | | 17alpha-estradiol induces aromatase activity in intact human anagen hair follicles ex vivo.[Pubmed: 12190948] |
METHODS AND RESULTS:
For topical treatment of androgenetic alopecia (AGA) in women, solutions containing either estradiol benzoate, estradiol valerate, 17beta- or 17alpha-Estradiol are commercially available in Europe and some studies show an increased anagen and decreased telogen rate after treatment as compared with placebo. Because aromatase is involved in the conversion of testosterone to estrogens and because there is some clinical evidence that aromatase activity may be involved in the pathogenesis of AGA, we addressed the question whether aromatase is expressed in human hair follicles and whether 17alpha-Estradiol is able to modify the aromatase activity. Herewith we were able to demonstrate that intact, microdissected hair follicles from female donors express considerably more aromatase activity than hair follicles from male donors. Using immunohistochemistry, we detected the aromatase mainly in the epithelial parts of the hair follicle and not in the dermal papilla. Furthermore, we show that in comparison to the controls, we noticed in 17alpha-Estradiol-incubated (1 nM) female hair follicles a concentration- and time-dependent increase of aromatase activity (at 24 h: 1 nM = +18%, 100 nM = +25%, 1 micro M = +57%; 24 h: 1 nM = +18%, 48 h: 1 nM = +25%).
CONCLUSIONS:
In conclusion, our ex vivo experiments suggest that under the influence of 17alpha-Estradiol an increased conversion of testosterone to 17beta-estradiol and androstendione to estrone takes place, which might explain the beneficial effects of estrogen treatment of AGA. |
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| In vivo: |
| J Alzheimers Dis. 2002 Dec;4(6):449-57. | | 17Alpha-estradiol and 17beta-estradiol treatments are effective in lowering cerebral amyloid-beta levels in AbetaPPSWE transgenic mice.[Pubmed: 12515896] | Post-menopausal estrogen therapy is associated with a decreased incidence of Alzheimer disease and in vitro models have shown that 17beta-estradiol is effective in lowering amyloidogenic processing.
METHODS AND RESULTS:
To examine the effects of estrogen withdrawal and replacement on amyloid beta (Abeta) levels and amyloid beta-protein precursor (AbetaPP) processing in vivo, Swedish mutant AbetaPP transgenic mice were ovariectomized or sham ovariectomized at four weeks of age and treated with placebo or 17beta- or 17alpha-Estradiol pellets, the latter being a weak estrogen receptor agonist. Compared to sham ovariectomized mice, ovariectomy with placebo did not alter Abeta levels; however, the levels of Abeta were decreased by 27% and 38% in mice treated with 17beta- and 17alpha- estradiol, respectively, with no change in AbetaPP holoprotein. Endogenous and exogenous estrogen both significantly increased the levels of sAbetaPPalpha, the secreted form of AbetaPP. The ratio of Abeta/sAbetaPPalpha, a measure of amyloidogenic processing, was reduced in all estrogen-containing groups. The Abeta lowering effect of 17beta- and 17alpha-Estradiol was replicated when estrogens were administered at a more physiological dose in the drinking water, or when mice were ovariectomized at three months of age.
CONCLUSIONS:
The increased efficacy of 17alpha-Estradiol versus 17beta-estradiol may help to develop safe and effective therapeutics. | | Exp Neurol. 2008 Mar;210(1):41-50. | | 17α-estradiol is neuroprotective in male and female rats in a model of early brain injury[Pubmed: 17997403 ] | One of the most critical times in the human lifespan is the late embryonic/early postnatal period, due to the careful orchestration of numerous events leading to normal brain development. This period is also characterized by a heightened incidence of harmful events that act via the GABAergic system, including hypoxia-ischemia, seizures and drug exposure from maternal circulation (e.g., alcohol, barbiturates). Unfortunately, there are few effective means of attenuating damage in the immature brain.
METHODS AND RESULTS:
In the current investigation, we documented the effect of 17alpha-Estradiol, a natural epimer of 17beta-estradiol that has potent estrogen receptor-independent actions, on excessive GABA(A) receptor-induced damage to the neonatal brain. We observed that treatment with 17alpha-Estradiol significantly attenuates the GABA(A) receptor-induced reduction in hippocampal volume and impaired hippocampal-dependent performance on the Morris water maze and radial arm maze. 17alpha-Estradiol-mediated neuroprotection is hypothesized to be achieved by attenuating GABA(A) receptor-induced cell loss, assessed in primary hippocampal cultures using both the lactate dehydrogenase assay and TUNEL, with equivalent prevention of cell loss in the presence or absence of the estrogen receptor antagonist, ICI-182,780.
CONCLUSIONS:
These data highlight one of the initial investigations of the neuroprotective potential of 17alpha-Estradiol in an in vivo model of injury to the immature brain. |
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