Brain-Derived Estrogen and Neurological Disorders

SIMPLE SUMMARY: Classically, 17β-estradiol, the most potent estrogen produced in the body, is considered to be an endocrine hormone, which is produced primarily in the ovaries in females and circulates in the blood to regulate target tissues throughout the body. However, a large body of research has revealed that both astrocytes and neurons create substantial levels of 17β-estradiol in the brains of both males and females. The roles and functions of brain-derived 17β-estradiol have been an area of intense study, and due to advances in techniques and animal models much progress has been made in understanding its actions and importance in the normal and injured/diseased brain. In this review, we examine evidence that brain-derived 17β-estradiol has primarily a beneficial neuroprotective and anti-inflammatory role in various neurological insults and disorders that affect the brain, including stroke, brain injury, Alzheimer’s disease and Parkinson’s disease. We also discuss evidence that brain-derived 17β-estradiol may have detrimental effects in certain situations, especially when over-produced, such as in epilepsy. Finally, we also explore potential future directions for the area and review the distinct functions and mechanisms of action of 17β-estradiol generated from neurons versus astrocytes. ABSTRACT: Astrocytes and neurons in the male and female brains produce the neurosteroid brain-derived 17β-estradiol (BDE(2)) from androgen precursors. In this review, we discuss evidence that suggest BDE(2) has a role in a number of neurological conditions, such as focal and global cerebral ischemia, traumatic brain injury, excitotoxicity, epilepsy, Alzheimer’s disease, and Parkinson’s disease. Much of what we have learned about BDE(2) in neurological disorders has come from use of aromatase inhibitors and global aromatase knockout mice. Recently, our group developed astrocyte- and neuron-specific aromatase knockout mice, which have helped to clarify the precise functions of astrocyte-derived 17β-estradiol (ADE(2)) and neuron-derived 17β-estradiol (NDE(2)) in the brain. The available evidence to date suggests a primarily beneficial role of BDE(2) in facilitating neuroprotection, synaptic and cognitive preservation, regulation of reactive astrocyte and microglia activation, and anti-inflammatory effects. Most of these beneficial effects appear to be due to ADE(2), which is induced in most neurological disorders, but there is also recent evidence that NDE(2) exerts similar beneficial effects. Furthermore, in certain situations, BDE(2) may also have deleterious effects, as recent evidence suggests its overproduction in epilepsy contributes to seizure induction. In this review, we examine the current state of this quickly developing topic, as well as possible future studies that may be required to provide continuing growth in the field.