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 www.nel.edu
More
information available: publisher@nel.edu
