title: "All in the mind"? Brain-targeting chemical delivery system of 17β-estradiol (Estredox) produces significant uterotrophic side effect.
abstract: Here we revisit the peculiarly named redox chemical delivery system concept. This unique prodrug approach has long been claimed to be capable of targeting 17β-estradiol (E2), which has numerous beneficial central effects, into the brain without detrimental peripheral hormonal exposure. Using a well-established protocol to monitor E2's antidepressant-like effect, we show that the administration of this chemical delivery system incorporated into hydroxypropyl-β-cyclodextrin (i.e., Estredox), indeed, triggers a transient antidepressant-like behavior in ovariectomized mice. At the same time, even an acute dose of the carefully purified chemical delivery system produces significant circulating E2 levels and uterotrophic side effects for several days after drug administration. For the first time, we also unequivocally show by liquid chromatography coupled with tandem mass spectrometry that the uterus of the Estredox-treated animals contains a large quantity of E2 compared to that of the control group. These thus far unexposed yet consequential peripheral side effects brought about by Estredox call for a thorough and unbiased reassessment of the extent of brain-targeting of the hormoneviathe chemical delivery system approach.
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, United States ; Department of Pharmaceutical Sciences, University of North Texas System College of Pharmacy, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, United States.
authors.forename: Katalin
authors.initials: K
authors.lastname: Prokai-Tatrai
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, United States.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Szarka
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, United States.
authors.forename: Vien
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, United States.
authors.forename: Fatima
authors.initials: F
authors.lastname: Sahyouni
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, United States.
authors.forename: Cary
authors.initials: C
authors.lastname: Walker
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, United States.
authors.forename: Shastazia
authors.initials: S
authors.lastname: White
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, United States.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Talamantes
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, United States.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Prokai
keywords: 17β-estradiol; Estredox; LC-MS/MS; Porsolt swim test; chemical delivery system; circulating 17β-estradiol; peripheral side effect; uterotrophic effect