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Bazedoxifene - a promising brain active SERM that crosses the blood brain barrier and enhances spatial memory.

Authors
  • Hill, R A1
  • Kouremenos, K2
  • Tull, D2
  • Maggi, A3
  • Schroeder, A4
  • Gibbons, A4
  • Kulkarni, J5
  • Sundram, S4
  • Du, X6
  • 1 Department of Psychiatry, Monash University, Clayton, VIC, 3168, Australia; Florey Institute for Neuroscience and Mental Health, Parkville, VIC, 3052, Australia. Electronic address: [email protected] , (Australia)
  • 2 Metabolomics Australia, Bio21 Molecular Science & Biotechnology Institute, Parkville, VIC, 3052, Australia. , (Australia)
  • 3 Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, 20133, Italy. , (Italy)
  • 4 Department of Psychiatry, Monash University, Clayton, VIC, 3168, Australia. , (Australia)
  • 5 Monash Alfred Psychiatry Research Centre, Monash University, St Kilda, VIC, 3004, Australia. , (Australia)
  • 6 Department of Psychiatry, Monash University, Clayton, VIC, 3168, Australia; Florey Institute for Neuroscience and Mental Health, Parkville, VIC, 3052, Australia. , (Australia)
Type
Published Article
Journal
Psychoneuroendocrinology
Publication Date
Aug 17, 2020
Volume
121
Pages
104830–104830
Identifiers
DOI: 10.1016/j.psyneuen.2020.104830
PMID: 32858306
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Over 20 years of accumulated evidence has shown that the major female sex hormone 17β-estradiol can enhance cognitive functioning. However, the utility of estradiol as a therapeutic cognitive enhancer is hindered by its unwanted peripheral effects (carcinogenic). Selective estrogen receptor modulators (SERMs) avoid the unwanted effects of estradiol by acting as estrogen receptor antagonists in some tissues such as breast and uterus, but as agonists in others such as bone, and are currently used for the treatment of osteoporosis. However, understanding of their actions in the brain are limited. The third generation SERM bazedoxifene has recently been FDA approved for clinical use with an improved biosafety profile. However, whether bazedoxifene can enter the brain and enhance cognition is unknown. Using mice, the current study aimed to explore if bazedoxifene can 1) cross the blood-brain barrier, 2) rescue ovariectomy-induced hippocampal-dependent spatial memory deficit, and 3) activate neural estrogen response element (ERE)-dependent gene transcription. Using liquid chromatography-mass spectrometry (LC-MS), we firstly demonstrate that a peripheral injection of bazedoxifene can enter the brain. Secondly, we show that an acute intraperitoneal injection of bazedoxifene can rescue ovariectomy-induced spatial memory deficits. And finally, using the ERE-luciferase reporter mouse, we show in vivo that bazedoxifene can activate the ERE in the brain. The evidence shown here suggest bazedoxifene could be a viable cognitive enhancer with promising clinical applicability. Copyright © 2020 Elsevier Ltd. All rights reserved.

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