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

Laszlo Prokai, Vien Nguyen, Szabolcs Szarka, Puja Garg, Gauri Sabnis, Heather A. Bimonte-Nelson, Katie J. McLaughlin, Joshua S. Talboom, Cheryl D. Conrad, Paul J. Shughrue, Todd D. Gould, Angela Brodie, Istvan Merchenthaler, Peter Koulen, Katalin Prokai-Tatrai

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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. We show that a small-molecule bioprecursor prodrug, 10b,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 that 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. Together, 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.

Original languageEnglish
Article number297ra113
JournalScience Translational Medicine
Volume7
Issue number297
DOIs
StatePublished - 22 Jul 2015

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Prodrugs
Estradiol
Estrogens
Brain
Menopause
Hormones
Psychiatry
Uterus
Rodentia
Animal Models
Stroke
Gene Expression
Therapeutics
Growth

Cite this

Prokai, Laszlo ; Nguyen, Vien ; Szarka, Szabolcs ; Garg, Puja ; Sabnis, Gauri ; Bimonte-Nelson, Heather A. ; McLaughlin, Katie J. ; Talboom, Joshua S. ; Conrad, Cheryl D. ; Shughrue, Paul J. ; Gould, Todd D. ; Brodie, Angela ; Merchenthaler, Istvan ; Koulen, Peter ; Prokai-Tatrai, Katalin. / The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders. In: Science Translational Medicine. 2015 ; Vol. 7, No. 297.
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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. We show that a small-molecule bioprecursor prodrug, 10b,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 that 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. Together, 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.",
author = "Laszlo Prokai and Vien Nguyen and Szabolcs Szarka and Puja Garg and Gauri Sabnis and Bimonte-Nelson, {Heather A.} and McLaughlin, {Katie J.} and Talboom, {Joshua S.} and Conrad, {Cheryl D.} and Shughrue, {Paul J.} and Gould, {Todd D.} and Angela Brodie and Istvan Merchenthaler and Peter Koulen and Katalin Prokai-Tatrai",
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Prokai, L, Nguyen, V, Szarka, S, Garg, P, Sabnis, G, Bimonte-Nelson, HA, McLaughlin, KJ, Talboom, JS, Conrad, CD, Shughrue, PJ, Gould, TD, Brodie, A, Merchenthaler, I, Koulen, P & Prokai-Tatrai, K 2015, 'The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders', Science Translational Medicine, vol. 7, no. 297, 297ra113. https://doi.org/10.1126/scitranslmed.aab1290

The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders. / Prokai, Laszlo; Nguyen, Vien; Szarka, Szabolcs; Garg, Puja; Sabnis, Gauri; Bimonte-Nelson, Heather A.; McLaughlin, Katie J.; Talboom, Joshua S.; Conrad, Cheryl D.; Shughrue, Paul J.; Gould, Todd D.; Brodie, Angela; Merchenthaler, Istvan; Koulen, Peter; Prokai-Tatrai, Katalin.

In: Science Translational Medicine, Vol. 7, No. 297, 297ra113, 22.07.2015.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders

AU - Prokai, Laszlo

AU - Nguyen, Vien

AU - Szarka, Szabolcs

AU - Garg, Puja

AU - Sabnis, Gauri

AU - Bimonte-Nelson, Heather A.

AU - McLaughlin, Katie J.

AU - Talboom, Joshua S.

AU - Conrad, Cheryl D.

AU - Shughrue, Paul J.

AU - Gould, Todd D.

AU - Brodie, Angela

AU - Merchenthaler, Istvan

AU - Koulen, Peter

AU - Prokai-Tatrai, Katalin

PY - 2015/7/22

Y1 - 2015/7/22

N2 - 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. We show that a small-molecule bioprecursor prodrug, 10b,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 that 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. Together, 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.

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