Estrogenic Regulation of Neuroprotective and Neuroinflammatory Mechanisms: Implications for Depression and Cognition

Abstract

Glial cells, such as astrocytes and microglia, contribute to maintain tissue homeostasis in the brain and are involved in the control of neuronal function, synaptic plasticity, and neuroinflammation. In the aged brain and under neurodegenerative conditions, microglial cells acquire a senescent reactive phenotype, which involves a dysregulated inflammatory response that affects the normal function and metabolism of neurons and other cell types, including astrocytes. The impaired function of astrocytes and microglia in the aged brain increases neuroinflammation, which is associated with depressive disorders and cognitive deficits. Estradiol, from gonadal origin or locally produced in the brain, exerts anti-inflammatory actions in the central nervous system, regulating the reactive phenotype of astrocytes and microglia. In addition, estrogen receptor signaling exerts direct neuroprotective actions on neurons and interacts with the signaling of other neuroprotective and anti-inflammatory factors in the brain. These actions of estradiol and estrogen receptors contribute to maintain a proper neuronal information processing, promoting cognitive function and preventing affective disorders. The effects of estradiol are imitated by synthetic estrogenic compounds, such as some selective estrogen receptor modulators and tibolone.