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

R. A. Hill, K. Kouremenos, D. Tull, A. Maggi, A. Schroeder, A. Gibbons, J. Kulkarni, S. Sundram, X. Du

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number104830
Number of pages9
JournalPsychoneuroendocrinology
Volume121
DOIs
Publication statusPublished - Nov 2020

Keywords

  • Bazedoxifene
  • blood-brain barrier
  • cognition
  • estrogen receptor
  • estrogen response element
  • hippocampus

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