The antioxidative effect of the Δ-dehydro derivative of 17α-estradiol, 14α,15α-methylene-8-dehydro-17α-estradiol (J861), was studied in comparison with 17α- and 17β-estradiols in the liver of cholesterol-fed rabbits.The radical scavenging properties of the scavestrogen estra-1,3,5(10),8-tetraene-3,17α-diol (J811) and the estradiol isomers and J861 in vitro were evaluated using spin-trapping techniques.Male rabbits were fed a standard diet containing stock pellet and vegetables.All the estrogens were found to be effective interceptors of free oxygen radicals.The decrease in the concentration of spin trap-radical adducts showed that the scavenging efficacy of the estrogens was increased in the following order: 17β-estradiol < 17α-estradiol < J811 < J861.The feeding of cholesterol developed a prooxidant effect, increasing all the measured radical-related parameters.The chemiluminescence attenuated by lucigenin reflects HO^- generation but can also be induced by reactions with other reactive oxygen species.The high antiatherogenic effects of J861 in comparison with 17α-estradiol and 17β-estradiol are probably due to its marked radical scavenging and antioxidative properties.

01 Jan 2001·ClimactericQ4 · MEDICINE

Antiatherogenic effects of 17β-estradiol and 17α-estradiol and its derivative J811 in cholesterol-fed rabbits with thyroid inhibition

Q4 · MEDICINE

Article

Author: I. Chirkina ; E. Naruta ; A. Chirkin ; O. Lukivskaya ; D. Hübler ; V. U. Buko ; M. Oettel ; W. Römer ; Y. Popov

OBJECTIVEThe aim of this study was to investigate the antiatherogenic effects of 17 beta-estradiol and 17 alpha-estradiol and its derivative J811 (estra-1,3,5(10),8-tetraene-3, 17 alpha-diol), having a non-feminizing effect and high antioxidant potential, in male rabbits.EXPERIMENTAL DESIGNMale White-Russian rabbits weighing 2.1-2.6 kg were fed either a standard or a high-cholesterol (200 mg/kg) diet, with thyroid function-inhibiting thiouracil (20 mg/kg) combined with cholic acid (40 mg/kg) administered daily in sunflower oil for 3 months. During the last month of the study, estrogens were administered by gavage at a dose of 0.02 or 0.1 mg/kg.RESULTS AND CONCLUSIONSAll three estrogens exerted remarkable antiatherosclerotic effects. Decreases in serum and aortic-wall lipid parameters and the index of atherogenicity were dependent on estrogen dose. Morphological evaluation of the aortic wall (height of plaques, size of plaque relative to aortic half-circumference) showed only weak therapeutic effects with all three estrogens. It is an open question whether the treatment period was too short to reverse the above changes. On the other hand, the data clearly suggest that 17 alpha-estradiol and J811 offer new perspectives for the prevention of atherosclerosis in men, which is similar to that found with 17 beta-estradiol in women.

15 Nov 2000·Journal of Neuroscience ResearchQ3 · MEDICINE

Antioxidants J811 and 17?-estradiol protect cerebellar granule cells from methylmercury-induced apoptotic cell death

Q3 · MEDICINE

Article

Author: L. Manzo ; B. Zhivotovsky ; E. Daré ; M.E. Götz ; S. Ceccatelli

Cerebellar granule cells (CGC) have provided a reliable model for studying the toxicity of methylmercury (MeHg), a well-known neurotoxicant contaminating the environment. In the present study we report that doses of MeHg ranging from 0.1 microM to 1.5 microM activated apoptosis, as shown by cell shrinkage, nuclear condensation, and formation of high-molecular-weight DNA fragments. Nevertheless, caspase-3-like activity was not significantly induced, and the broad caspase inhibitor Z-VAD-FMK was not capable of protecting the cells. This argues for a minor role of caspases in the intracellular pathways leading to MeHg-induced cell death in CGC. Instead, proteolytic fragments obtained by specific calpain cleavage of procaspase-3 and alpha-fodrin were increased consistently in samples exposed to MeHg, pointing to a substantial activation of calpain. Notably, two antioxidants, 17beta-estradiol (10 microM) and the Delta(8,9)-dehydro derivative of 17alpha-estradiol J811 (10 microM), protected from MeHg damage, preventing morphological alterations, chromatin fragmentation, and activation of calpain. These findings underscore the key role of oxidative stress in MeHg toxicity, placing it upstream of calpain activation. The shielding effect of the 17beta-estradiol and the radical scavenger J811 is potentially relevant for the development of therapeutic strategies for MeHg intoxication.

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Indication	Highest Phase	Country/Location	Organization	Date
Menopausal syndrome	Preclinical	DE	Jenapharm GmbH & Co. KG	-

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