Phyllis M. Wise, Ph.D.
University of Kentucky

Estradiol is a Neuroprotective Factor in the Aging Brain: Mechanisms of Action.

Estrogen appears to protect the aging brain against cognitive dysfunction, neurodegenerative diseases, and brain injury such as stroke. The menopause is accompanied by a dramatic and permanent decrease in estrogen levels. During the past century, the longevity of women has increased from 50 to over 80 years. But, the age of the menopause has remained constant and occurs when women are about 50 years of age. This means that after women undergo the menopause, they will be hypoestrogenic for over thirty years of their lives, and may consequently suffer from an increased vulnerability to a variety of diseases. It is, therefore, crucial that we understand how estradiol acts to protect the brain against these diseases so that we can design drugs that exert only protective actions of estradiol, and do not have detrimental side effects. Since high doses of estradiol can have unwanted side effects, the longterm goal of our studies is to understand the molecular mechanisms by which low, physiological levels of estradiol replacement protect the brain.

We have previously discovered that low levels of estradiol replacement exert profound protective effects in the brain. Using an animal model of stroke, we found that estradiol dramatically decreases the degree of brain injury in adult and in aging female rats. Therefore, the proposed studies are designed to uncover how estradiol acts to protect the brain. First, we will assess the molecular mechanisms of estradiolís protective actions in vivo using wild-type and ER*KO mice combined with DNA array technology. This specific aim seeks to identify the repertoire of genes that are influenced by estradiol in a model of brain injury. Second, we will determine whether the neuroprotective actions of estradiol in in vitro explant cultures of the cerebral cortex of wild-type and ER*KO mice parallel in vivo observations. We will use explant cultures of cerebral cortex to determine whether we can replicate estradiolís protective actions in an in vitro model of brain injury. Third, we will verify changes in gene statement detected through array technology using in situ hybridization and real-time PCR methods. It is clear that this new and powerful method must be verified using other methods before data can be considered trustworthy. Finally, we will assess whether estradiolís protective effects result from receptor-mediated actions on neurons or astrocytes by using the Cre-Lox mouse system to selectively knockout ER in neurons or astrocytes.

In summary, our proposed studies focus on novel, non-reproductive actions of estradiol in the brain. The results will provide new information regarding mechanisms underlying estradiol-dependent enhancement of neuronal viability. They carry profound and exciting possibilities in the future treatment of brain injury and cognitive disorders in elderly women.

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