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Bazedoxifene – a promising brain active SERM that crosses the blood brain barrier and enhances spatial memory
- Source :
- Psychoneuroendocrinology. 121:104830
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
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.
- Subjects :
- Selective Estrogen Receptor Modulators
Indoles
Endocrinology, Diabetes and Metabolism
Hippocampus
Estrogen receptor
Pharmacology
Blood–brain barrier
Estrogen Receptor Antagonists
Bazedoxifene
Mice
03 medical and health sciences
Cognition
0302 clinical medicine
Endocrinology
In vivo
medicine
Animals
Biological Psychiatry
Spatial Memory
Hormone response element
Estradiol
Endocrine and Autonomic Systems
business.industry
Brain
Estrogens
030227 psychiatry
Mice, Inbred C57BL
Psychiatry and Mental health
medicine.anatomical_structure
Blood-Brain Barrier
Selective estrogen receptor modulator
Female
business
hormones, hormone substitutes, and hormone antagonists
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 03064530
- Volume :
- 121
- Database :
- OpenAIRE
- Journal :
- Psychoneuroendocrinology
- Accession number :
- edsair.doi.dedup.....ff408062f3e7d15714ad13d68343eec3