A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease

Abstract

Estrogens are neuroprotective and, thus, potentially useful for the therapy of Alzheimer’s disease; however, clinical use of hormone therapy remains controversial due to adverse peripheral effects. The goal of this study was to investigate the benefits of treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective prodrug of 17β-estradiol, in comparison with the parent hormone using APPswe/PS1dE9 double transgenic mice to model the pathology of the disease. Ovariectomized and intact females were continuously treated with vehicle, 17β-estradiol, or DHED via subcutaneous osmotic pumps from 6 to 8 months of age. We confirmed that this prolonged treatment with DHED did not stimulate uterine tissue, whereas 17β-estradiol treatment increased uterine weight. Amyloid precursor protein decreased in both treatment groups of intact, but not in ovariectomized double transgenic females in which ovariectomy already decreased the expression of this protein significantly. However, reduced brain amyloid-β peptide levels could be observed for both treatments. Consequently, double-transgenic ovariectomized and intact mice had higher cognitive performance compared to untreated control animals in response to both estradiol and DHED administrations. Overall, the tested brain-selective 17β-estradiol prodrug proved to be an effective early-stage intervention in an Alzheimer’s disease-relevant mouse model without showing systemic impact and, thus, warrants further evaluation as a potential therapeutic candidate.

The mechanism(s) of action of antioxidants: From scavenging reactive oxygen/nitrogen species to redox signaling and the generation of bioactive secondary metabolites

“…In contrast, luteolin (9) itself reached only a F I G U R E 6 Cyclic antioxidant mechanism for estrone and estradiol, involving a chemically stable, p-quinol intermediate formed through • OH radical scavenging. DHED was successfully applied in vivo as a brain-targeted neuroprotective pro-drug of estradiol [147][148][149] HUNYADI | 2515 0.6 nM/mL peak plasma concentration in that study, and its concentration in the organs was also typically below that of 9c. 124 Unlike luteolin, its glycosides reach the large intestine where the sugar moieties can efficiently be cleaved by gut bacteria.…”

“…Prokai et al found that • OH radical scavenging by estrone yields a p ‐quinol A‐ring‐containing intermediate that subsequently undergoes a NADP‐dependent enzymatic reduction back to estrone, without contributing to oxidative stress on its own but becoming able to scavenge further radicals . In vivo administration of the analogous p ‐quinol derivative of estradiol (DHED) demonstrated no estrogenic activity, and it was rapidly taken up into the brain where it initiated the above‐mentioned redox cycle; therefore it acted as a targeted neuroprotective agent without any apparent systemic side‐effects . On one hand, this provides an attractive strategy to deliver estrogens to the brain through their pro‐drugs.…”

“…Cyclic antioxidant mechanism for estrone and estradiol, involving a chemically stable, p ‐quinol intermediate formed through • OH radical scavenging. DHED was successfully applied in vivo as a brain‐targeted neuroprotective pro‐drug of estradiol…”

“…[144][145][146] In vivo administration of the analogous p-quinol derivative of estradiol (DHED) demonstrated no estrogenic activity, and it was rapidly taken up into the brain where it initiated the above-mentioned redox cycle; therefore it acted as a targeted neuroprotective agent without any apparent systemic side-effects. [147][148][149][150] On one hand, this provides an attractive strategy to deliver estrogens to the brain through their pro-drugs. On the other hand, it also represents a good example for a phenolic antioxidant (estradiol or estrone) to be transformed to a metabolite (eg DHED) on a free radical scavenging-related manner.…”

Sex Hormones and Alzheimer’s Disease

“…Moreover, female CSF-E2 level is positively correlated with CSF-Aβ level and cerebral glucose metabolism in the left hippocampus PET scan, which denotes that they are at increased risk to develop AD. In short-term studies, transdermal estrogen administration is associated with increased attention, verbal and visual memories; however, long-term studies failed to slow down AD progression or adding benefits to rivastigmine therapy in postmenopausal women [47,81].…”