The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders

Abstract

Many neurological and psychiatric maladies originate from the deprivation of the human brain from estrogens. However, current hormone therapies cannot be used safely to treat these conditions commonly associated with menopause because of detrimental side-effects in the periphery. The latter also prevents the use of the hormone for neuroprotection. Here we show that a small-molecule bioprecursor prodrug, 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), converts to 17β-estradiol in the brain after systemic administration, but remains inert in the rest of the body. The localized and rapid formation of estrogen from the prodrug was revealed by a series of in vivo bioanalytical assays and through in vivo imaging in rodents. DHED treatment efficiently alleviated symptoms originated from brain estrogen deficiency in animal models of surgical menopause and provided neuroprotection in a rat stroke model. Concomitantly, we determined that 17β-estradiol formed in the brain from DHED elicited changes in gene expression and neuronal morphology identical to those obtained after direct 17β-estradiol treatment. Altogether, complementary functional and mechanistic data show that our approach is highly relevant therapeutically, because administration of the prodrug selectively produces estrogen in the brain independently from the route of administration and treatment regimen. Therefore, peripheral responses associated with the use of systemic estrogens, such as stimulation of the uterus and estrogen-responsive tumor growth, were absent. Collectively, our brain-selective prodrug approach may safely provide estrogen neuroprotection and medicate neurological and psychiatric symptoms developing from estrogen deficiency, particularly those encountered after surgical menopause, without the adverse side-effects of current hormone therapies.

ERβ-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid

“…For this, the focus of several studies has turned to synthetic ligands that selectively activate ERb and are thus devoid of undesired carcinogenic effects (47). A previous study highlights the use of the prodrug DHED that is metabolized to estradiol selectively in the brain and could have valuable therapeutic effects on human diseases associated with estrogen-mediated neuroprotection (48), such as multiple sclerosis. In addition, very recent studies by our group shed light on the ERb ligand-mediated regulation of CNS autoimmunity and of Th17 responses, via ERb expression on CD4 + T cells.…”

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

“…DHED was prepared according to previously published procedures (Prokai et al, 2015). All other chemicals were purchased from Sigma-Aldrich (St. Louis, MO) unless otherwise stated.…”

“…This study is focused on the AD-therapeutic potential of a novel brain-selective E2 prodrug, 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), that spares the periphery from estrogenic stimulation (Prokai et al, 2015). Specifically, we aimed at determining whether DHED treatment would slow the progression of the onset of AD characteristics, including the reduction of Aβ formation and protection against cognitive impairment, by directly comparing with the efficacy of E2 treatment in a well-characterized double-transgenic (DTG) mouse model of the disease (Jankowsky et al, 2004).…”

Modeling menopause: The utility of rodents in translational behavioral endocrinology research

“…In addition, we have the advantageous capacity to evaluate behavioral and brain changes at the cellular and molecular level much more quickly than would be possible using human subjects. This utility affords basic scientists the opportunity to explore novel brain targets and drug delivery methods [136] for favorable cognitive outcomes and healthy brain aging profiles that have the potential to translate to the clinical research setting.…”