In
recent times, estrogen has been labeled as a protective and/or
destructive cellular messenger. In our review, we attempt
to understand this discrepancy. In 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 suggests that
this hormone plays a pivotal role in retarding and preventing
the formation of neurodegenerative diseases through its receptor.
Gaining a better understanding of these estrogen receptor
mediated neuroprotective mechanisms may lead to new therapeutic
strategies for the treatment of neurodegenerative diseases,
which are a heterogeneous group of diseases of the nervous
system that have many different etiologies. Due to the prevalence,
morbidity and mortality of the neurodegenerative diseases,
they represent significant medical, social, and financial
burdens.
These
diseases are often age associated, chronic and progressive
with limited treatment modalities. It is usually noted in
many epidemiological studies that premenopausal women experience
greater protection from neurological diseases, but articulating
the precise biological mechanisms for this gender difference
in disease risk and onset has remained elusive. Although multiple
complex factors may be involved, the role of the hormone estrogen
and its receptor has remained one of the central focuses of
investigation since postmenopausal women enjoy none of the
same protection against neurological diseases as those who
are premenopausal.
The
significance of estrogen, as an important signaling molecule,
is demonstrated by our recent findings in this issue of Neuroendocrinology
Letters in that this molecule is also present in invertebrate
neural tissues. We not only demonstrate 17-b-estradiol’s
presence via mass spec, but also find a fragment of the estrogen
receptor-b gene, exhibiting 100%
sequence identity to that found in man. Here, it appears to
down regulate ganglionic microglial cells after surgical insult,
which normally stimulates their egress from the tissue. Additionally,
17-b- estradiol down regulates
these cells following fMLP activation. These actions are antagonized
by tamoxifen and L-NAME exposure, demonstrating a receptor-mediated
event, as well as one involving nitric oxide release, supporting
a cell surface role for estrogens action. The results show
that 17-b-estradiol can down regulate
invertebrate ganglionic glia cells, demonstrating a neural
role transcending reproduction.
In
the last report in this issue, we sought to determine if estrogen
is found in Mytilus reproductive tissues. We determined the
presence of 17-b-estradiol via
high pressure liquid chromatography and radioimmunoassay in
the animals’ gonads. This substance was further identified
via nanoelectro-spray ionization quadrupole time of flight
mass spectrometry. We also determined that estradiol isoforms
also were present in the tissue. These data demonstrate that
17-b-estradiol, and an estradiol
isoform, is present in Mytilus gonadal tissues, suggesting
that they have functions related to reproduction. This further
suggests that estrogen’s association with reproductive
activities has a long evolutionary history and that this association
began in invertebrates.
We
further speculate that estrogen signaling was essential for
animals, including invertebrates, because it was a messenger
involved with rhythmical/cyclic regulatory patterns, involving
tissue growth. It is ideally suited for this role because
it has a long half-life, which allows it to reach nuclear
targets, i.e., genomic processes. Here, cell surface signaling,
i.e., nongenomic processes, may also be important, and part
of estrogen’s signaling repertoire, since it modulates
cell activation states, i.e., down regulating, so that growth
can occur in an optimum microenvironment. Thus, by down regulating
a cells general activity, i.e., mobility, it allows the cells
to focus its "attention" on growth/reproduction
when appropriate. This process would enable the genomic nature
of estrogen’s signaling to take place since the cells
are in a more receptive state. This action of the cell surface
receptors also serves to conserve energy in order to focus
energy on reproductive associated growth processes.
The
finding of estrogen signaling in invertebrates highlights
the molecules evolutionary significance. This, in itself,
urges caution in interpreting its role in biomedical situations.
