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Department of Reproductive Medicine, University of California-San Diego School of Medicine, La Jolla, California 92093-0633
Address all correspondence and requests for reprints to: Ismail Zwain, Ph.D., Department of Reproductive Medicine, BSB-5045, University of California-San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0633. E-mail: izwain{at}ucsd.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxylase/C17–20-lyase (P450c17), 3ß-hydroxysteroid
dehydrogenase (3ßHSD), 17ß-hydroxysteroid dehydrogenase (17ßHSD),
and cytochrome P450 aromatase (P450arom) and produce pregnenolone (P5),
progesterone (P4), dehydroepiandrosterone (DHEA),
androstenedione (A4), testosterone (T), estradiol, and estrone.
Oligodendrocytes express only P450scc and 3ßHSD and produce P5, P4,
and A4. These cells do not express P450c17, 17ßHSD, or P450arom or
produce DHEA, T, or estrogen. Neurons express P450scc,
P450c17, 3ßHSD, and P450arom and produce P5, DHEA, A4,
and estrogen, but do not express 17ßHSD or produce T. By comparing
the ability of each cell type in the production of neurosteroids,
astrocytes are the major producer of P4, DHEA, and
androgens, whereas oligodendrocytes are predominantly the producer of
P5 and neurons of estrogens. These findings serve to define the
neurosteroidogenic pathway, with special emphasis on the dominant role
of astrocytes and their interaction with oligodendrocytes and neurons
in the genesis of DHEA and active sex steroids. Thus, we
propose that neurosteroidogenesis is accomplished by a tripartite
contribution of the three cell types in the brain. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxylase/C17–20-lyase (P450c17) and produce DHEA
(10). The previous attempts to demonstrate the presence of P450c17 in
astrocytes in culture were unsuccessful (8, 34), as we have shown that
the contaminant microglial cells in the cell cultures play a critical
role in the biosynthesis of DHEA (10). In the presence of
these residual cells, astrocytes produced a negligible concentration of
DHEA. Eradication of microglia from astrocyte cell
cultures resulted in a dramatic increase in DHEA
production (10). The 3ß-hydroxysteroid dehydrogenase (3ßHSD) enzyme responsible for the production of progesterone (P4) and androstenedione (A4) was also identified in several regions of adult rat brain (3, 5, 11, 12) and was suggested to be expressed in glial cells (6). Anther key steroidogenic enzyme, 17ß-hydroxysteroid dehydrogenase (17ßHSD), which catalyzes the conversion of A4 to testosterone (T), was also reported in rat and mouse brain tissue (13, 14, 15). In recent studies, we demonstrated cytochrome P450 aromatase (P450arom), mRNA, and activity in cortical and hypothalamic astrocytes of rat brain (10, 16).
Although these studies presented evidence that brain is indeed a steroidogenic organ by its ability to express steroidogenic enzymes and produce neurosteroids in vitro, the steroidogenic pathway in astrocytes, oligodendrocytes, and neurons and the relative contribution of these cells to neurosteroidogenesis has not been characterized. The present study was designed to assess the differential gene expression of the key steroidogenic enzymes, including P450scc, P450c17, 3ßHSD, 17ßHSD, and P450arom, and the production of neurosteroids by cortical astrocytes, oligodendrocytes, and neurons.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The
presence of contaminant endothelial in glial cell cultures was
investigated by immunocytochemical analysis of factor VIII protein. No
immunoreactive cells were found in the cell cultures. The
immunocytochemical analysis of Leu M5 protein, a
microglia/macrophage-specific protein marker, was also performed to
determine whether microglia cells are eradicated from glial cell
cultures. No microglia cells were detected in glial cell cultures after
LME treatment and successive plating of glial cells in culture flasks.
Before treatment of glial cells with LME, astrocyte and oligodendrocyte
cell cultures contained 5% and 3% Leu M5-immunostained cells,
respectively. No contaminant neurons were detected in the glial cell
cultures as determined by immunocytochemical analysis of neurofilament
protein.
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Isolation and culture of neurons. Neuronal culture was
performed as previously described by Hertz et al. (23) with
modification. Briefly, cerebral cortical tissue from 1-day-old rat
brains was mechanically dispersed, and cells were cultured in medium
containing 20% horse serum for 3 days at 37 C in culture plates
precoated with poly-L-lysine substrates. Cell cultures were
then exposed for 24 h to cytosine arabinoside (40
µM) to eliminate the nonneuronal cells, including
microglia and macroglia cells (astrocytes and oligodendrocytes). To
remove any possible remaining contaminant microglia, neurons were
successively plated three times with systematic changing of culture
plates as described above. Neurons were then cultured in precoated
plates in SFM. After 48 h in culture, neurons were washed and
cultured for an additional 48 h in SFM with various treatments.
The purity of the neurons was 99%, as judged by immunocytochemical
analysis of neurofilament protein (Sigma Chemical Co., St.
Louis, MO), a specific protein marker for neurons (Fig. 1
). No
endothelial, microglial, or glial cells were detected in the neuronal
cell cultures, as determined by immunocytochemical analysis.
The purity of isolated neurons, glial cells, astrocytes, and oligodendrocytes was analyzed using cells from three different experiments. Before treatment of cells with steroids, six-well culture plates containing astrocytes, oligodendrocytes, and neurons (one plate of each cell type from each experiment) were randomly selected for assessment of cell purity by immunocytochemical analysis. The isolated cells in the three experiments showed the same percentage of purity (99%).
Preparation of samples
At the conclusion of culture, astrocytes, oligodendrocytes, and
neurons were removed by mild trypsinization, and cell viability was
determined by trypan blue staining. Media from astrocyte,
oligodendrocyte, and neuron cultures were collected, centrifuged, and
stored at -20 C until analysis of DHEA, progesterone,
androstenedione, testosterone, estrone, and estradiol concentrations
using a RIA kit (Diagnostic Systems Laboratories, Inc.,
Webster, TX). The pregnenolone assay was performed using a RIA kit
purchased from ICN Biochemicals, Inc. (Costa Mesa, CA).
The cross-reactivity of the antisera used in the assay of steroids was
determined by the manufacturers of the RIA kits. The minimum detection
limit and intra- and interassay variations of P5, DHEA,
P4, A4, T, estradiol (E2), and estrone
(E1) were determined using in-house assays. The
minimum detection limits were 25, 24, 90, 70, 60, 2.1, and 3.2 pg/ml;
the intraassay variations were 9.13%, 5.86%, 9.25%, 5.70%, 9.60%,
4.85%, and 4.29%; and the interassay variations were 14.16%, 9.09%,
3.79%, 8.70%, 12.86%, 8.66%, and 5.64%, respectively.
Total RNA from cultured cells was isolated using the guanidine phenol-chloroform extraction method and were treated with deoxyribonuclease to remove contaminant DNA. Samples were then stored at -70 C until analysis of the gene expression of steroidogenic enzymes by RT-PCR. The integrity of the RNA was demonstrated by analyzing ribosomal RNAs using ethidium bromide staining.
RT-PCR
RT-PCR analysis of steroidogenic enzymes was performed as
previously described by Zwain et al. (16). Briefly, 2 µg
total RNA were reverse transcribed using Moloney murine leukemia virus
RT (Perkin Elmer, Branchburg, NJ) in the presence of
oligo(deoxythymidine) primer. One tenth of the RT reaction was used as
a template for amplification by PCR using AmpliTaq Gold DNA polymerase
(Perkin Elmer). Amplification was performed in a
Perkin Elmer thermal cycler with the following cycling
parameters: initial activation of the AmpliTaq Gold DNA polymerase at
95 C for 11 min, denaturation at 94 C for 45 sec, annealing at 60 C for
1 min, and extension at 72 C for 2 min. A total of 35 cycles were used,
followed by a 10-min final extension at 72 C. The specific sense and
antisense oligonucleotide PCR primers for P450scc, P450c17, 3ßHSD,
17ßHSD, and P450arom are shown in Table 1. PCR products were resolved on 2%
agarose gel, stained with ethidium bromide, and visualized under UV
light. The identities of PCR products were further confirmed by
restriction digestion and Southern blot analyses as previously
described (16).
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Statistical analysis
Student’s unpaired t test was used when only two
groups were compared. For multiple comparisons, data were analyzed by
one-way ANOVA with post-hoc Bonferroni test using the
Statistical Analysis System (StatView software, SAS Institute, Inc., Chicago, IL). Each experiment was repeated two or three
times using three replicate cultures for each data point, and the
statistical analysis of each set of experiments showed the same
results. Results are expressed as the mean ±
SD of three replicate cultures. Some data shown
no SD because data of the replicate cultures were
so similar. P < 0.05 was considered statistically
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, lane 1), oligodendrocytes (Fig. 2A, lane 2), and neurons (Fig. 2A, lane 3). P450c17 was expressed in
astrocytes (Fig. 2B, lane 1) and neurons (Fig. 2B, lane 3), but not in
oligodendrocytes (Fig. 2B, lane 2). 3ßHSD was detected in astrocytes
(Fig. 2C, lane 1), oligodendrocytes (Fig. 2C, lane 2), and neurons
(Fig. 2C, lane 3). 17ßHSD was only expressed in astrocytes (Fig. 2D, lane 1), whereas other cells were negative (Fig. 2D, lanes 2 and 3).
P450arom was expressed in astrocytes (Fig. 2E, lane 1) and neurons
(Fig. 2E, lane 3). Oligodendrocytes showed no mRNA for P450arom (Fig. 2E, lane 2).
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, lanes 4) and testicular (lanes 5) tissue of adult rats
abundantly expressed P450scc, P450c17, 3ßHSD, 17ßHSD, and P450arom
(Figs. 2A, 1B, 1C, 1D, and 1E, respectively). The sizes of the RT-PCR
products of all steroidogenic enzymes in astrocytes, oligodendrocytes,
and neurons were identical to those in ovarian and testicular tissue.
The PCR products of steroidogenic enzymes in astrocytes,
oligodendrocytes, and neurons as well as in ovarian and testicular
tissue were further confirmed by Southern blot analysis using specific
internal oligonucleotide probes and by restriction digestion analysis
(data not shown). The restriction digestion analysis of RT-PCR products
of steroidogenic enzymes in the three cell types of the brain and in
ovarian and testicular tissue showed identical DNA fragments. The
negative control samples where reverse transcriptase was omitted from
the RT-PCR reaction showed no PCR products (data not shown), confirming
the specificity of the PCR amplification.
Neurosteroidogenic activity
The neurosteroidogenic activity of P450scc, P450c17, 3ßHSD,
17ßHSD, and P450arom was evaluated by determining the ability of
cortical microglia-free astrocytes, oligodendrocytes, and neurons to
produce neurosteroids in the presence of steroid substrates. RIA was
used to quantify steroid production by each cell type.
P450scc. Cortical astrocytes, oligodendrocytes, and neurons
converted cholesterol into P5 in a dose-dependent manner (Fig. 3, A–C). However, oligodendrocytes were
much more active than astrocytes and neurons in the production of P5.
At a dose of 10-6 M cholesterol, the
production of P5 by oligodendrocytes was 3- and 8-fold higher than that
by astrocytes and neurons, respectively. Cortical neurons produced low
levels of P5.
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, A and C, left panel).
However, astrocytes were more active than neurons in the production of
DHEA. At a concentration of 10-6
M P5, DHEA production by astrocytes was 10
times higher than that by neurons. Oligodendrocytes were not able to
convert P5 into DHEA (Fig. 4B, left panel). The
production of DHEA is not limited to cerebral cortical
astrocytes, as hypothalamic astrocytes were also able to convert P5
into DHEA in a dose-dependent manner (data not shown). The
P450c17 activity was further confirmed by the ability of astrocytes and
neurons, but not oligodendrocytes, to convert P4 into A4 in a
dose-dependent fashion (Fig. 4, A–C, right panel).
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). We also evaluated the
specificity of P450c17 activity in astrocytes by blocking its
biosynthesis using antisense oligonucleotide specific to P450c17 cDNA.
Treatment of astrocytes with the antisense oligonucleotide resulted in
a dose-dependent decrease in DHEA production by astrocytes
compared with that in the control cells cultured without treatment. The
sense oligonucleotide was without effect (Fig. 5B). By semiquantitative
RT-PCR using ß-actin as an internal standard, the antisense, but not
the sense, oligonucleotide has been demonstrated to induce significant
inhibition of gene expression of P450c17 compared with the control
(data not shown). These data confirm the specificity of the antisense
effect.
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, A–C,
left panel) and P5 to P4 (Fig. 6, A–C, right
panel) in a dose-dependent manner. Astrocytes were the most active
in the conversion of DHEA to A4 and P5 to P4. Production
of A4 and P4 by astrocytes was specific, as the addition of trilostane,
the 3ßHSD inhibitor, to the culture medium resulted in a significant
inhibition of the conversion of DHEA to A4 (Fig. 7A) and P5 into P4 (Fig. 7B).
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). Neither
cortical oligodendrocytes (Fig. 8B) nor neurons (Fig. 8A) produced T.
The specificity of T production by cortical astrocytes was evaluated by
blocking the biosynthesis of 17ßHSD by antisense oligonucleotide
specific to 17ßHSD cDNA. Conversion of A4 to T by astrocytes was
inhibited in a dose-dependent manner by treatment of cells with the
antisense oligonucleotide compared with that in the untreated cells,
whereas the sense oligonucleotide was without effect (Fig. 9). By semiquantitative RT-PCR using
ß-actin as an internal standard, the antisense, but not the sense,
oligonucleotide has been demonstrated to induce significant inhibition
of gene expression of 17ßHSD compared with the control (data not
shown). These data confirm the specificity of the antisense effect.
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, A and C, left panel) and
A4 to E1 (Fig. 10, A and C, right
panel) in a dose-dependent manner. However, neurons were more
active than astrocytes in the aromatization of androgen to estrogen.
Oligodendrocytes do not produce either E2 (Fig. 10B, left panel) or E1 (Fig. 10B, right panel). The antisense oligonucleotide technology was
also used to confirm the specificity of estrogen production by
astrocytes. Treatment of astrocytes with the antisense oligonucleotide
to P450arom cDNA resulted in a dose-dependent inhibition of the
aromatization of T to E2 (Fig. 11) compared with that in the untreated
cells. The sense oligonucleotide was without effect. By
semiquantitative RT-PCR using ß-actin as an internal standard,
the antisense, but not the sense, oligonucleotide has been demonstrated
to induce significant inhibition of gene expression of P450arom
compared with that in the control (data not shown). These data confirm
the specificity of the antisense effect.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We also showed for the first time that oligodendrocytes express another key steroidogenic enzyme, 3ßHSD, and are able to convert P5 to P4 and DHEA to A4. The expression of 3ßHSD and the production of P4 and A4 have also been demonstrated in astrocytes and neurons, confirming previous studies reporting the production of P4 from P5 by astrocytes (6) and the presence of 3ßHSD and its mRNA in neurons (3, 12).
The production of P4 from P5 by Schwann cells in the peripheral nervous system has been reported (29). Schwann cells share several metabolic characteristics of oligodendrocytes, including myelin formation (1, 29). However, it is not known whether P4 is also involved in myelin formation in the central nervous system and whether it acts directly on neurons or indirectly through oligodendrocytes. Oligodendrocytes have been shown to express myelin proteins, myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase, which are involved in myelin formation (30). As in Schwann cells, P4 was shown to stimulate the expression of myelin proteins in oligodendrocytes (30). Thus, it is possible that as in the peripheral nervous system, P4 may also be involved in myelin formation in the CNS via activation of oligodendrocytes to produce proteins that are necessary for the myelination. Although oligodendrocytes are predominant in the production of P5, the substrate for P4, these cells are less active than astrocytes in the production of P4. This may be due to the low 3ßHSD enzymatic activity in oligodendrocytes compared with that in astrocytes. Astrocytes and oligodendrocytes may interact with each other to fulfill their requirements of P4 and P5 that are necessary for their functional activities. In this context, astrocytes may provide oligodendrocytes with additional P4, which may be required in the myelination process. Equally, oligodendrocytes may serve as an additional source of P5 for astrocytes to produce P4 and DHEA. Further studies are required to address these issues.
We have also demonstrated that the P450c17 enzyme that catalyzes the conversion of P5 to DHEA is expressed in cortical astrocytes and neurons. However, the presence of this enzyme in brain was a matter of controversy. Compagnone et al. (31) detected P450c17 mRNA in rat and mouse embryonic brain tissues and in whole brain and cerebral cortical tissue of young adult rat brains (4, 5, 32). In contrast to these studies, P450c17 protein (33), mRNA (8), and activity (34) were not detected in adult rat brain tissues. Moreover, mixed glial cells and astrocytes from rat and mouse embryo brains in cultures did not express P450c17 mRNA (8) and were unable to metabolize radioactive P5 to DHEA (34). In a recent study, we demonstrated that residual contaminant microglia cells in the cultures dramatically inhibit the production of DHEA by astrocytes in vitro (10). By eradication of microglial cells from the cell cultures, astrocytes and neurons become active and produce DHEA (10). Microglial cells were found to be the major contaminants cell type (5%) in the primary astrocyte cell cultures (10, 19). There was no particular effort made by previous studies (8, 34) to eradicate microglial cells from astrocyte cell cultures, and this may explain their failure to detect P450c17, mRNA, and its activity in vitro. Although, microglial-free astrocytes and neurons produce DHEA, the gene expression of P450c17 in these cells is low, as it is only detectable by RT-PCR, suggesting that contaminant microglial cells inhibited P450c17 mRNA to a level below the detection limit of PCR. However, the production of DHEA by these cells, particularly astrocytes, is relatively high, suggesting a potent enzymatic activity for P450c17 in these cells.
The inhibition of DHEA production by astrocytes and
neurons in culture by microglial cells would not explain the lack of
P450c17 and its activity in brain as reported by some in
vivo studies. In the brain, cellular activity is under the control
of a complex interaction of multiple factors, including growth factors,
hormones, cytokines, neuropeptides, neurotransmitters, and steroids,
that may not exist in the culture dish. The exact mechanism by which
microglial cells inhibit DHEA production by astrocytes and
neurons in culture is unknown. Microglial cells secret factors such as
nitric oxide (NO), tumor necrosis factor- (TNF), and
interleukin-1ß (IL-1ß), which are known to be potent inhibitors of
gene expression and androgen production in gonads (35, 36, 37, 38). The
production of NO by microglial cells requires activation of these cells
by lipopolysaccharides or ß-amyloid (39). However, microglial cells
have also been shown to be activated by IL-1 and TNF to produce NO.
IL-1 increases the production and gene expression of TNF (40),
which, in turn, stimulates NO release by microglial cells (41).
Further, NO has shown to stimulate TNF production by microglial
cells (41). Based on these studies, cytokines and NO can act mutually
to stimulate each other in microglial cells. Thus, it is possible that
in response to a signal from microglial cells itself or from astrocytes
or neurons in the culture dish, microglial cells become activated and
produce high concentrations of cytokines and NO. The possibility that
microglial cells may produce other unknown factors that directly
inhibit P450c17 gene expression and consequently DHEA
production by astrocytes and neurons in culture should also be
considered. Further studies are required to address these issues.
The role and significance of DHEA in the brain are not yet known. However, several functional activities have been reported for DHEA in the brain, including modulation of neurotransmitters (42, 43), enhancing memory and learning of adult rats (44, 45), and protection of neurons from damage during some neurodegenerative disorders (46, 47). Additionally, DHEA serves as a substrate for androgen and estrogen biosynthesis by cortical and hypothalamic astrocytes (10). T and E2 are known to play crucial roles in sexual behavior, neuronal differentiation, and growth (for review, see Ref. 48).
Two other key steroidogenic enzymes, 17ßHSD (13, 14, 15) and P450arom (49, 50), have been reported in tissues obtained from several regions of rat brain. Data from the present study demonstrated for the first time that astrocytes are the only sites for expression of 17ßHSD and production of T from A4 in the brain. Neurons and oligodendrocytes are devoid of 17ßHSD and are unable to produce T. We also presented evidence that astrocytes and neurons, but not oligodendrocytes, express P450arom and produce E2 and E1 from T and A4, respectively. Neurons appear to be more active than astrocytes in aromatization of androgen to estrogen. As neurons are not able to produce T, it is therefore possible that astrocytes provide T for neurons to produce E2.
In addition to the steroidogenic enzymes reported in this study, brain
has been shown to express several other enzymes, including steroid
sulfotransferase, 17-hydroxysteroid dehydrogenase,
5-reductase, 3-hydroxysteroid dehydrogenase, and
7-hydroxylase, that are required for metabolism of P5, P4, and
androgen (1, 51). However, the significance of the biosynthesis of
these enzymes and their steroid byproducts in the brain is not known,
and further studies are required.
Summary and conclusion
As illustrated in Fig. 12, astrocytes are the most active steroidogenic cells in the brain, as
these cells express P450scc, P450c17, 3ßHSD, 17ßHSD, and P450arom
and produce P5, P4, DHEA, androgens, and estrogens.
Oligodendrocytes only express P450scc and 3ßHSD and produce P5 and
P4. Neurons express the same steroidogenic enzymes and produce the same
neurosteroids as astrocytes, with the exception of expression of
17ßHSD enzyme and production of T. These data revealed that
astrocytes, oligodendrocytes, and neurons have differential capacities
in the production of neurosteroids, suggesting that these cells may
interact with each other to fulfill their contributions for a full
steroidogenic pathway. Oligodendrocytes produce P5 at a level much
higher than that in astrocytes, but are less active in the production
of P4 that is required for activation of myelin protein formation in
oligodendrocytes (30). Astrocytes possess the enzymatic activities to
actively convert P5 into P4 and DHEA, which both serve as
direct substrates for androgen and estrogen biosynthesis. However,
astrocytes produce a small amount of P5 compared with oligodendrocytes.
It is therefore possible that oligodendrocytes and astrocytes exchange
P5 and P4 that are necessary for maintaining their functional
activities (Fig. 12). Although neurons are more active than astrocytes
in the aromatization of androgen to estrogen, they lack the enzymatic
activity of 17ßHSD and are unable to produce T, the direct substrate
for E2 biosynthesis. Astrocytes may therefore
play an indirect role in the aromatization process in neurons by
providing the substrate T (Fig. 12). We propose that
neurosteroidogenesis in the cerebral cortex of the neonatal rat brain
is accomplished by a tripartite contribution of the three cell types:
astrocytes, oligodendrocytes, and neurons. Further studies are required
to validate this theory and determine whether neurosteroidogenesis in
the brain is region specific and/or age dependent.
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Footnotes |
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Received November 5, 1998.
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References |
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 X. Yue, M. Lu, T. Lancaster, P. Cao, S.-I. Honda, M. Staufenbiel, N. Harada, Z. Zhong, Y. Shen, and R. Li Brain estrogen deficiency accelerates A{beta} plaque formation in an Alzheimer's disease animal model PNAS, December 27, 2005; 102(52): 19198 - 19203. [Abstract] [Full Text] [PDF]
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 J. Simard, M.-L. Ricketts, S. Gingras, P. Soucy, F. A. Feltus, and M. H. Melner Molecular Biology of the 3{beta}-Hydroxysteroid Dehydrogenase/{Delta}5-{Delta}4 Isomerase Gene Family Endocr. Rev., June 1, 2005; 26(4): 525 - 582. [Abstract] [Full Text] [PDF]
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J. M. Wang, P. B. Johnston, B. G. Ball, and R. D. Brinton The Neurosteroid Allopregnanolone Promotes Proliferation of Rodent and Human Neural Progenitor Cells and Regulates Cell-Cycle Gene and Protein Expression J. Neurosci., May 11, 2005; 25(19): 4706 - 4718. [Abstract] [Full Text] [PDF]
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 D. N. Abrous, M. Koehl, and M. Le Moal Adult Neurogenesis: From Precursors to Network and Physiology Physiol Rev, April 1, 2005; 85(2): 523 - 569. [Abstract] [Full Text] [PDF]
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 V. D. Doan, S. Gagnon, and V. Joseph Prenatal blockade of estradiol synthesis impairs respiratory and metabolic responses to hypoxia in newborn and adult rats Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2004; 287(3): R612 - R618. [Abstract] [Full Text] [PDF]
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A. F. Keller, J.-D. Breton, R. Schlichter, and P. Poisbeau Production of 5{alpha}-Reduced Neurosteroids Is Developmentally Regulated and Shapes GABAA Miniature IPSCs in Lamina II of the Spinal Cord J. Neurosci., January 28, 2004; 24(4): 907 - 915. [Abstract] [Full Text] [PDF]
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Y. Hojo, T.-a. Hattori, T. Enami, A. Furukawa, K. Suzuki, H.-t. Ishii, H. Mukai, J. H. Morrison, W. G. M. Janssen, S. Kominami, et al. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017{alpha} and P450 aromatase localized in neurons PNAS, January 20, 2004; 101(3): 865 - 870. [Abstract] [Full Text] [PDF]
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 N. Azad, S. Pitale, W. E. Barnes, and N. Friedman Testosterone Treatment Enhances Regional Brain Perfusion in Hypogonadal Men J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3064 - 3068. [Abstract] [Full Text] [PDF]
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C. Ibanez, R. Guennoun, P. Liere, B. Eychenne, A. Pianos, M. El-Etr, E.-E. Baulieu, and M. Schumacher Developmental Expression of Genes Involved in Neurosteroidogenesis: 3{beta}-Hydroxysteroid Dehydrogenase/{Delta}5-{Delta}4 Isomerase in the Rat Brain Endocrinology, July 1, 2003; 144(7): 2902 - 2911. [Abstract] [Full Text] [PDF]
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S. R. King, P. R. Manna, T. Ishii, P. J. Syapin, S. D. Ginsberg, K. Wilson, L. P. Walsh, K. L. Parker, D. M. Stocco, R. G. Smith, et al. An Essential Component in Steroid Synthesis, the Steroidogenic Acute Regulatory Protein, Is Expressed in Discrete Regions of the Brain J. Neurosci., December 15, 2002; 22(24): 10613 - 10620. [Abstract] [Full Text] [PDF]
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 O. Pascual, M.-P. Morin-Surun, B. Barna, M. Denavit-Saubie, J.-M. Pequignot, and J. Champagnat Progesterone reverses the neuronal responses to hypoxia in rat nucleus tractus solitarius in vitro J. Physiol., October 15, 2002; 544(2): 511 - 520. [Abstract] [Full Text] [PDF]
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P. S. Quadros, J. L. Pfau, A. Y. N. Goldstein, G. J. De Vries, and C. K. Wagner Sex Differences in Progesterone Receptor Expression: A Potential Mechanism for Estradiol-Mediated Sexual Differentiation Endocrinology, October 1, 2002; 143(10): 3727 - 3739. [Abstract] [Full Text] [PDF]
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T. M. Saleh, A. E. Cribb, and B. J. Connell Estrogen-induced recovery of autonomic function after middle cerebral artery occlusion in male rats Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2001; 281(5): R1531 - R1539. [Abstract] [Full Text] [PDF]
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S. S. C. Yen Dehydroepiandrosterone sulfate and longevity: New clues for an old friend PNAS, July 17, 2001; 98(15): 8167 - 8169. [Full Text] [PDF]
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