Estrogen — Mystery Drug for the Brain?

General abbreviations.- 1. Introduction.- Estrogen — more than “just” a female sex hormone.- Estrogen is a hormone: but what are hormones, anyway?.- A little history.- In the beginning there was a physiological function.- … then there was the chemical structure.- … an estrogen binding-protein.- … and finally there was the cloning of the first estrogen receptor.- How do hormones act?.- Hormones.- Estrogen — THE sex hormone and more.- 2. Estrogen is a steroid.- Production of sex hormones in the gonadal glands.- Biosynthesis of sex hormones.- Hormonal changes during the female puberty and the menstrual cycle.- Transport of estradiol in the bloodstream and catabolism.- 3. Estrogen acts via receptors.- “Estrogen’s classics” — the genomic pathway of estrogen action.- Steroid receptors have a complex protein structure.- Another level of complexity: estrogen acts via two ERs (ER? and ER?).- ER? and ER?: a basic comparison.- The structural domains of ER? and ER?.- Modulation of the estrogen receptor function.- Interaction of the ER with co-activators and co-repressors: of RIPs, RAPs and DRIPs.- Selective estrogen receptor modulators – SERMs.- To be or not to be? Are there membrane ERs?.- 4. “Non-classical” activities of estrogen.- Rapid non-genomic effects compared to slow genomic effects of steroid hormones: what makes the difference?.- Rapid effects of estrogen.- Structure-dependent effects: estradiol as antioxidant.- Reactive oxygen species (ROS): normal byproducts of life under oxygen.- Antioxidant defense lines of the cell.- Estradiol is an antioxidant similar to ?-tocopherol (vitamin E).- Dietary phenols and the blood-brain-barrier.- 5. General physiological activities of estrogen.- Lessons from the ERKO-mice.- 6. Estrogen’s actions in the brain.- Estrogen receptors in the brain.- Neuroactivities of estrogens in brain areas outside the hypothalamus: the effect of sex differences.- Effects of estrogen on the cholinergic system.- Effects of estrogen on the serotonergic and catecholaminergic system.- Activities of estrogen on glial cells.- Are there gender differences in brain function?.- Sexual differentiation and gross gender differences in brain structure and function.- Sex differences in the function of the hippocampus.- “Non-classical” activities of estrogen in the brain.- Estrogen as “neuroactive steroid” and estradiol’s non-genomic effects at neuronal membranes 79 Estrogen’s “cross-talks” with the intracellular signaling in neurons.- Estrogen and MAP kinase signaling.- Estrogen’s “cross-talk” with other signal pathways in neurons.- Estrogen is a phenolic antioxidant.- The pathogenetic role of oxidative stress in the CNS.- The brain is particularly sensitive to oxidative stress.- 7. Protection of the brain by estrogen.- Estrogen as drug for the brain?.- Menopause, and estrogen replacement therapy (ERT).- ERT for age-related degenerative diseases: general remarks.- Estrogen and human diseases: general beneficial effects of estrogen.- Estrogen and arteriosclerosis.- Estrogen and osteoporosis.- Estrogen as a drug for the treatment and prevention of brain diseases?.- Effects of estrogen on cognition.- Estrogen in neuropsychiatric disorders.- Neurodegenerative disorders — Alzheimer’s Disease.- What is the cause of AD?.- Various AD-hypotheses.- The estrogen-Alzheimer link.- Parkinson’s Disease.- PD and estrogen.- Novel approaches for the treatment of PD.- Stroke.- Stroke and estrogen.- Schizophrenia.- Depression.- To replace or not to replace? ERT and breast cancer risk.- 8. Nerve cell protection by estrogen: molecular mechanisms.- Life is difficult, at the cellular and molecular level, too.- Protective effect of estrogen in cultured neuronal cells.- Mechanisms of nerve cell death.- The two main routes to cell death: apoptosis and necrosis.- Executioners of apoptosis: caspases.- How to detect apoptosis?.- Is there apoptosis in Alzheimer’s Disease?.- Apoptosis in post-mortem AD brain tissue.- Apoptosis and necrosis of nerve cells in culture (in vitro).- AD genetics and apoptosis.- Investigations of estrogen’s neuroprotective activities in vitro.- Intracellular molecular mechanisms of neuroprotection by estrogen.- Direct ER-dependent neuroprotection: induction of neuroprotective genes.- “Cross-Talks” of estradiol with neuroprotective signaling.- MAP-kinase signaling.- Phosphatidylinositol 3 (PI3)-kinase.- NF-?B.- NF-?B is an oxidative stress-responsive transcription factor.- NF-?B has anti-apoptotic and pro-apoptotic activities.- Cyclic AMP/CREB-signaling.- Intracellular Cat2+levels and electrophysiology.- Estradiol is a neuroprotective antioxidant: ER-independent effects.- Oxidative stress as a general trigger of nerve cell death.- Oxidative stress in neurodegeneration.- Estradiol is a neuroprotective antioxidant.- 9. Outlook.- Estrogen’s neuroprotective target genes and estrogen’s effects on neuronal stem cells.- Following the neuroprotective trace of estrogen.- DNA-array/gene chip technology and expression profiling.- Screening DNA-arrays/gene chips to identify estrogen target genes.- Estrogen and stem cells.- What are stem cells?.- Stem cells in the brain — the concept of mammalian neural stem cells and estrogen’s effects on neural stem cells.- Estrogen modulates neural stem cell generation.- Final remarks: neuroprotection by estrogen.- 10. References.