BE360, a new selective estrogen receptor modulator, produces antidepressant and antidementia effects through the enhancement of hippocampal cell proliferation in olfactory bulbectomized mice

Abstract

We have reported that the carborane compound BE360 is a novel selective estrogen receptor modulator and new therapy option for osteoporosis. The aim of this study was to explore the effects and underlying mechanisms of BE360 on depressive-like behavior and memory impairment in the olfactory bulbectomized (OBX) mice, an experimental animal model of depression and dementia. BE360 was administered subcutaneously to mice using a mini-osmotic pump for 2 weeks. Depressive-like behavior was measured as the reduced intake of a sweet solution in the sucrose preference test. Short-term memory was assessed using the Y-maze test. Cell proliferation was assessed by the analysis of cells expressing 5-bromo-2'-deoxyuridine (BrdU) uptake. The expression of phosphorylated cyclic-AMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were measured by immunoblot. The depressive-like behavior and memory impairment in OBX mice were improved by the chronic treatment with BE360. Immunohistochemical analysis showed that the number of BrdU-positive cells in the dentate gyrus of the hippocampus significantly decreased in OBX mice whereas they increased after the chronic treatment with BE360. Immunoblotting studies revealed that pCREB and BDNF were significantly increased in the hippocampus of OBX mice treated with BE360. The present study has shown that BE360 has antidepressant and antidementia effects characterized by hippocampal cell proliferation potentially activated via CREB/BDNF signaling pathways. These results indicate that BE360 may have valuable therapeutic potential against depression and neurodegenerative diseases.

Keywords: Carborane compound; Cell proliferation; Depression; Memory; Olfactory bulbectomy; Selective estrogen receptor modulator.