title: 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. 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 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.
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. AgyPharma LLC, Mansfield, TX 76063, USA. laszlo.prokai@unthsc.edu.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Prokai
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Vien
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Szarka
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. Vision Research Center and Departments of Ophthalmology and Basic Medical Science, University of Missouri-Kansas City, School of Medicine, Kansas City, MO 64108, USA.
authors.forename: Puja
authors.initials: P
authors.lastname: Garg
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Gauri
authors.initials: G
authors.lastname: Sabnis
authors.affiliation: Department of Psychology, Arizona State University, Tempe, AZ 85287, USA. Arizona Alzheimer's Consortium, Tempe, AZ 85014, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Bimonte-Nelson
authors.affiliation: Department of Psychology, Arizona State University, Tempe, AZ 85287, USA.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: McLaughlin
authors.affiliation: Department of Psychology, Arizona State University, Tempe, AZ 85287, USA. Arizona Alzheimer's Consortium, Tempe, AZ 85014, USA.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Talboom
authors.affiliation: Department of Psychology, Arizona State University, Tempe, AZ 85287, USA.
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Conrad
authors.affiliation: Department of Pharmacology, Elan Pharmaceuticals Inc., South San Francisco, CA 94080, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Shughrue
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Gould
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Brodie
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Merchenthaler
authors.affiliation: Vision Research Center and Departments of Ophthalmology and Basic Medical Science, University of Missouri-Kansas City, School of Medicine, Kansas City, MO 64108, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Koulen
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. AgyPharma LLC, Mansfield, TX 76063, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Prokai-Tatrai
mesh_terms: D000734:Androstenediols / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism*; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D000066829:Neuroprotection / Q000187:drug effects; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D020521:Stroke / Q000150:complications / Q000188:drug therapy; D014599:Uterus / Q000187:drug effects
chemical_list: D000734:Androstenediols; D000928:Antidepressive Agents; D015415:Biomarkers; D004967:Estrogens; D011355:Prodrugs; C066747:3,16-dihydroxyandrost-5-ene-17,19-dione; D004958:Estradiol