Beneficial effects of physical exercise and an orally active mGluR2/3 antagonist pro-drug on neurogenesis and behavior in an Alzheimer's amyloidosis model

BCI-838 is a pro-drug whose active metabolite BCI-632 is an antagonist at the group II metabotropic glutamate receptor (mGluR2/3). Hippocampal dentate gyrus of four-month old mouse model of AD amyloid pathology (APP/PS1) were investigated via transcriptomics analysis following BCI-838 treatment and physical exercise. Findings demonstrate up-regulated brain-derived neurotrophic factor (BDNF), PIK3C2A of the PI3K-MTOR pathway, and metabotropic glutamate receptors, and down-regulated EIF5A of ketamine-modulating mTOR activity. Our study points to BCI-838 as a safe and orally active compound capable of mimicking the beneficial effect of exercise on AHN, learning behavior, and anxiety in a mouse model of AD neuropathology. Overall design: APP/PS1 mice were divided into four groups: Group 1 no exercise / no drug; Group 2 exercise / no drug; Group 3 exercise + drug; and Group 4 no exercise / drug. Group 5 consisted of WT mice (C57BL6/J). Groups receiving exercise were given ad libitum access to a running wheel and treatment with drug or vehicle was continued for one month. Two cohorts of mice were used. One cohort was used for behavioral analysis (n=12 mice per group) whereas a second was sacrificed for neurogenesis and biochemical studies (n=5 mice per group for each study).