Grant: Operating Grant

Evidence supports the prime importance of steroids in the maintenance of brain function during normal aging. Men/women differences and beneficial effects of estrogens are reported in several mental diseases and neurodegenerative diseases. With the increased life expectancy and the average age of menopause remaining constant, women can expect to live up to one half of their adult lives after menopause. Hormonal replacement therapy in menopausal women was widely used up to recent clinical studies that found more risks than benefits. No better alternative is available. We propose experiments in monkeys and mice to seek compounds with estrogenic activity or that could increase estrogens in the brain to protect, decrease, prevent or delay brain diseases like Parkinson disease. We propose to investigate the mechanism of action of these compounds. Our hypothesis is that we can find novel compounds beneficial for the brain with limited side effects from existing drugs used for endocrine diseases or based on a novel target in the brain, a recently found membrane estrogen receptor. Estrogen-like compounds targeting the brain may be useful for central nervous system symptoms associated with menopause. Raloxifene is an estrogenic drug used to treat osteoporosis in menopausal women; it will be tested for brain activity. Moreover, we seek gonadal drugs useful for central nervous system diseases in men without the feminizing effects of estrogens such as finasteride a gonadal drug used to treat benign prostate hyperplasia.