August 19, 2003
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Neuroendocrinology Letters incl. Psychoneuroimmunology & Chronobiology

including Psychoneuroimmunology, Neuro
Reproductive Medicine, Chronobiology
and Human Ethology
ISSN 0172–780X



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Preview next coming issue: Vol.24 Nos. 3/4,
Release date:
August 27, 2003
Is estrogen neuroprotective or neurodestructive
(George Stefano)

Is estrogen neuroprotective or neurodestructive:
Evolution may have the answer

Although the preponderance of studies investigating the effects of estrogen on vasomotor tone and function have focused on women, a number of recent studies have intriguingly shown that estrogen's rapid vasodilatory properties is also preserved in men. Unlike classical steroid genomic pathway, estrogen's acute vasodilatory effect is mediated by calcium dependent cell surface estrogen receptors that stimulate constitutive endothelial nitric oxide synthase (eNOS) activity, i.e., nongenomic. Stefano and colleagues in a series of reports in Neuroendocrinology Letters (NEL) state that partial or complete attenuation of this rapid signaling system can promote neuronal dysfunction, an early pathophysiological event.

In this regard, trying to rectify the differences in the risk, onset, and progression of neurodegenerative diseases between men and women, the gonadal hormone estrogen has been the primary focus of investigation for many years. Although this gender difference may encompass disparate and overlapping reasons, estrogen and signaling events mediated by its receptor have been shown to be neuroprotective in a number of neurodegenerative disease models such as Alzheimer's, Parkinson's, and Schizophrenia. Although data from human studies remains highly controversial, a large body of research findings suggests that this hormone plays a pivotal role in retarding and preventing the formation of neurodegenerative diseases through its receptor. By activating common intracellular signaling pathways and initiating "cross talk" with neurotrophins, estrogen plays an influential role in neuronal survival from injuries induced by ischemia or other environmental insults. Gaining a better understanding of these estrogen receptor mediated neuroprotective mechanisms may lead to new therapeutic strategies for the treatment of neurodegenerative diseases. Given the recent controversies regarding "neuro-estrogen" this review focuses and provides insights for the reader into pure estrogen actions that appear to be important in maintaining health.

The neuro-estrogen story is further highlighted by the fact it is present in animals that evolved 500 million years before man. Here, the NEL report demonstrates the following:

1) Mytilus pedal ganglia, a marine bivalve organism (clam-like), maintained in culture after surgical removal, over the course of 24 hours, emits microglia (connective tissue cells that protect nerve cells proper);

2) Estradiol significantly reduces the glial egress, keeping them down regulated;

3) Concomitant treatment of the ganglia with estradiol and an estrogen receptor antagonist, tamoxifen, or the nitric oxide synthase inhibitor L-NAME effectively restores the glial egress to the level found in control preparations;

4) Spontaneously active invertebrate microglia can be down regulated by estradiol.

Taken together these results suggest that endogenous estrogen may play a role in down regulating microglial activation and/or maintaining them in a down regulated state ready for activation, i.e., disinhibition, via nitric oxide. This also implies that if these cells are inappropriately activated estrogen may restore a proper level of activity. This in itself is a protective action.

Furthermore, this group of investigators identified by stringent biochemical means the presence of 17-b-estradiol in pedal ganglia of Mytilus. In addition, by Western blot analysis with anti-ER-b antibodies we observed a 55 kDa protein in both the membrane and cytosolic fractions in pedal ganglia as well as in human leukocytes (that have been previously shown to express estrogen receptor-b. In their current NEL report they demonstrate a fragment of estrogen receptor b sequence, which exhibits 100% sequence identity with that found in man. These data serve to demonstrate that estrogen signaling appeared much earlier along the evolutionary timetable than previously thought. Thus, this conservation of function further focuses attention on estrogen's positive neuroprotective role.

In addition, this group demonstrates that estradiol is present in Mytilus gonadal tissues and there appears to be an isoform of estradiol also present in this tissue, suggesting a complex role for the signaling family in this organism's reproductive system. Taken together, the study implicates estrogen signaling in invertebrate gonadal tissue, suggesting that its association with reproduction originated much earlier in evolutionary time than previously thought as well.

In mammals, the involvement of estrogen signaling in reproduction is a well documented phenomenon. The presence of this process, and signaling in invertebrates, represents new insight into its physiological significance, which also has biomedical ramifications. Why would invertebrates evolve such a process in the first place? The authors surmise that estrogen signaling evolved to meet the need for controlling tissue growth, which is rhythmical/cyclic in nature. Thus, estrogen is a multifaceted messenger that probably first arose by being an intracellular signaling molecule influencing processes that required a genomic substrate of action.


Abstract online: Expected date August 20, 2003

Issue is released in August 2003
Vol. 24 Nos. 3/4, 2003
Neuroendocrinology Letters

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