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The Journal of Neuroscience, December 1, 2000, 20(23):8604-8609
Estrogen Is Essential for Maintaining Nigrostriatal Dopamine
Neurons in Primates: Implications for Parkinson's Disease and
Memory
Csaba
Leranth1, 5,
Robert H.
Roth2, 3,
John D.
Elsworth2, 3,
Frederick
Naftolin1,
Tamas L.
Horvath1, 5, and
D. Eugene
Redmond Jr2, 4
Departments of 1 Obstetrics and Gynecology,
2 Psychiatry, 3 Pharmacology, and
4 Neurosurgery and 5 Section of Neurobiology,
Yale University, School of Medicine, New Haven, Connecticut 06520-8063
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ABSTRACT |
There are sexual differences in several parameters of the
nigrostriatal dopamine neurons, as well as in the progression of diseases associated with this system, e.g., Parkinson's disease and
dementia. These differences, as well as direct experimental data in
rodents, suggest that gonadal hormones play a role in modulating this
system. To determine whether circulating estrogen might have long-term
effects by altering the number of dopamine neurons, the density of
dopamine neurons was calculated in the compact zone of the substantia
nigra of male and intact female short- (10 d) and longer-term (30 d)
ovariectomized and short- and longer-term ovariectomized but
estrogen-replaced nonhuman primates (African green monkeys).
Furthermore, the number of tyrosine hydroxylase-expressing neurons, the
total number of all types of neurons, and the volume of the compact
zone of the substantia nigra were calculated in 30 d
ovariectomized and in 30 d ovariectomized and estrogen-replaced
monkeys. Unbiased stereological analyses demonstrated that a 30 d
estrogen deprivation results in an apparently permanent loss of >30%
of the total number of substantia nigra dopamine cells. Furthermore,
the density calculations showed that brief estrogen replacement
restores the density of tyrosine hydroxylase-immunoreactive cells after
a 10 d, but not after a 30 d, ovariectomy. Moreover, the density of dopamine cells is higher in females than in males. These
observations show the essential role of estrogen in maintaining the
integrity of the nigral dopamine system, suggest a new treatment strategy for patients with Parkinson's disease and with certain forms
of memory-impairing disorders, and provide another rationale for
estrogen replacement therapy for postmenopausal women.
Key words:
substantia nigra; African green monkey; ovariectomy; estrogen replacement; apoptosis; Parkinson's disease
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INTRODUCTION |
Gender differences are apparent in
the onset and progression of Parkinson's disease (PD). Estrogen
administration lowers the severity of symptoms of PD in postmenopausal
women with early onset of the disease and beneficially
affects certain types of memory impairments (Mayeux et al., 1992 ;
Sherwin, 1997; Saunders-Pullman et al., 1999). The primary motor
symptoms of PD and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism (Ehringer and Hornykiewicz,
1960) as well as PD-related dementia and other forms of memory
impairments (Ehringer and Hornykiewicz, 1960; Goldman-Rakic,
1998) in nonhuman primates are associated with the loss of
mesencephalic dopamine (DA) neurons. DA cell loss during normal aging
(Anglade et al., 1997) and in PD is associated, at least partly, with
apoptotic cell death (Burke and Kholodilov, 1998). Any strategy shown
to be effective in slowing or preventing DA cell loss should have an
important impact on these DA-related disorders. Laboratory observations
suggest that estrogen dramatically affects mesencephalic DA cells. A
number of gender differences in DA function in the striatum and nucleus
accumbens have been described in rodents (Becker, 1999). In female rats
estrogen and progesterone modulate DA activity, but in male rats
estrogen has no effect on striatal DA release. The DA content of
striatal tissue in this species is also higher in females than in males
(McDermott et al., 1994). Both tyrosine hydroxylase (TH) and DA
turnover rates are higher during diestrus (rising estrogen level) than
in estrus (low estrogen level) (Fernandez-Ruiz et al., 1991).
Furthermore, estrogen has a protective effect against MPTP-induced
neurotoxicity, including apoptosis, in mice (Dluzen et al., 1998).
These data clearly indicate that estrogen has an impact on the rodent
mesencephalic DA system. Most important, the finding that ovariectomy
(OVX) results in a profound reduction in the density and an
alteration in the morphology and distribution pattern of
TH-immunoreactive axons in the prefrontal cortex of monkeys (Kritzer
and Kohama, 1998) suggests that not only the integrity of axons but
also the parent neurons may be dependent on circulating ovarian
hormones. Because this information is relevant to human DA-dependent
disorders, the effect of estrogens on DA cell survival was addressed in
nonhuman primates. It is important to study primates because of the
similarity of menstrual cycles and the anatomical connections and
functions of the mesencephalic DA systems (Lewis and Sesack, 1997) in
humans and other primates.
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MATERIALS AND METHODS |
Young and adult female (n = 18) and male
(n = 3) African green monkeys (Cercopithecus
aethiops sabaeus; of reproductive age without stigmata of advanced
age) were used. The animals were housed in individual cages (water and
monkey chow were provided in excess of nutritional needs) at the St.
Kitts Biomedical Research Foundation (St. Kitts, West Indies). The
facility is in full compliance with all applicable United States
regulations, and treatment and care of these monkeys were in compliance
with the Guide for the Care and Use of Laboratory Animals
(1996, United States Public Health Service, Washington, DC: National Academy).
Female monkeys were divided into six experimental groups (three animals
in each group): (1) intact females, (2) females that were OVX
for 10 d (short-term) before killing, (3) short-term OVX plus
2 d estrogen treatment, (4) 30 d OVX plus 2 d estrogen treatment, (5) 30 d OVX, and (6) OVX with estrogen replacement for
30 d. The short-term (2 d) estrogen-treated monkeys
received a single injection of 150 µg of estradiol benzoate in 1 ml
of sesame oil. This dose of estradiol is known to elicit a
luteinizing-hormone surge (Karsch et al., 1973). The 30 d OVX plus
estrogen-replaced animals received two 4 cm estrogen-filled (100%
estradiol benzoate) SILASTIC capsules that were implanted below the
skin of the back, at the time of OVX. The 10 and 30 d OVX animals
did not receive vehicles (sesame oil or empty SILASTIC capsules,
respectively). According to our previous observations and those of
others, these treatments do not effect gonadal hormone levels in OVX
monkeys (Levine et al., 1985a,b; Leranth et al., 1992), but they
require anesthesia and cause probable transient nonspecific effects,
such as pain and discomfort associated with the procedures. Before killing the animals (by an overdose of pentobarbital), blood was collected from the female monkeys, and the serum estrogen level was measured by the use of radioimmunoassay (the sensitivity of the
radioimmunoassay used is >15 pg/ml). After rinsing the vascular system
with 1 l of 0.9% NaCl (with heparin, 1 U/ml), animals were transcardially perfused with 1500 ml of fixative containing 4% paraformaldehyde and 0.08% glutaraldehyde in phosphate buffer, pH
7.35. Brains were removed, and vibratome sections cut in a frontal
direction from the anteroposterior middle area of the substantia nigra
pars compacta (SNpc; 7-9 mm anterior from the interauricular line)
were immunostained for TH (all samples were run in a single batch)
(Leranth et al., 1998). Fifty-micrometer-thick vibratome sections were
cut from the substantia nigra of animals of experimental groups 1-5,
and a 1075 × 800 µm unit area (UA = 0.86 mm2) located lateral (3.22 mm) from the
midline and 7 mm above the interauricular line was video photographed
on each. The photographed field was in the center of a 3 × 1.8 mm
area of the SNpc, in which the cell density is homogeneous. On the
photographs (enlarged to 8.5 × 11 inches), only those
TH-immunoreactive neurons that contained at least a portion of the
nucleus (immunonegative) were counted. Sixteen to 18 sections were
counted for each monkey, with the first section selected randomly and
then every 10th section thereafter (pseudorandom sample). A two-factor
ANOVA test with repeated measures was used to analyze the significance
of differences between groups. Post hoc analysis was
performed by the Newman-Keuls test (SAS Institute, Cary, NC).
Furthermore, comparative light microscopic analysis was performed on
sections of the SNpc that were lightly immunostained for TH and
counterstained with cresyl violet from intact, 10 d OVX, 10 d
OVX plus estrogen-treated, and 30 d OVX plus estrogen-treated
females and males. Only the surface area of each vibratome section that
contained the immunostained neurons was analyzed because of the
possible variable penetration of TH antibody into the sections. Because
this distance cannot be quantified precisely, the resulting densities
are only valid comparatively across the groups in this study. For the
purpose of presenting the cell counts as density per unit volume, the volume was calculated from the 50-µm-thick section.
To confirm the comparative effects identified in the pars compacta,
unbiased stereological estimates of the density of all types of neurons
(stained with toluidine blue) and that of TH-immunoreactive cells were performed using the optical disector method (Gundersen et
al., 1988) in monkeys in experimental groups 5 and 6. These density
counts were then corrected for the total volume of the SNpc, calculated
by the method of Cavalieri (1966), to obtain values for the
total number of all neurons and TH-immunoreactive cells within the
SNpc. To perform this analysis, 40 µm serial vibratome sections were
cut throughout the compact zone of the SN, and every 10th section was
stained with toluidine blue, whereas the remaining sections were
immunostained for TH. After staining, dehydrating, and coverslipping
the sections with Permount, the final section thickness was measured
with a z-axis micrometer, and the boundaries of the SNpc
were drawn for each section using a drawing tube. Thereafter, a
point-counting grid was superimposed over the drawing of each section,
and the volume of the SNpc (V) was calculated
according to the formula: V =  P × a(P) × t, where a(P) is the area between grid points
(corrected for magnification), P is the number of grid
points lying within the boundaries of the SNpc, and t is the
thickness of the SNpc (average section thickness × number of
sections). The total number of SNpc neurons and that of
TH-immunoreactive cells were determined using the optical disector
method by counting stained cells in all sections of the series within a
5 × 30 × 30 µm sampling box. The position of counting
boxes was selected within each section in a systematic-random manner.
Counts obtained from the sampling boxes were then extrapolated to the
entire volume of the SNpc to yield the total cell number. The central
feature of these techniques is the use of a systematic-random sampling
that meets the statistical requirements necessary to insure an unbiased
estimate of the feature of interest. After appropriate preliminary
tests of distribution and variance, t tests were used to
determine differences between these two groups.
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RESULTS |
The density of TH-immunoreactive DA-producing neurons located in
identical areas of the compact zone of the substantia nigra of young
adult male, intact female, short- (10 d) and longer-term (1 month) OVX female, and short- and longer-term OVX plus
estrogen-treated animals were compared (Fig.
1). The level of circulating
estrogen in both 10 and 30 d OVX monkeys was <15 pg/ml. After a
2 d estrogen treatment of 10 and 30 d OVX animals, the
estrogen levels increased to 420-490 pg/ml. Statistical analyses
(Table 1) demonstrated that (1)
the DA cell density in the SNpc of intact females, males, and
short-term OVX females that received estrogen 2 d before killing was significantly higher than that of OVX-only animals, (2) no significant difference was observed between the decrease of SNpc DA
cell density of 10 and 30 d OVX females, (3) intact female monkeys
had a higher SNpc DA cell density than did males, and (4) estrogen
replacement for 30 d appears to prevent the loss of DA neurons
(Table 2). Comparative light microscopic
analyses demonstrated that in the 10 d OVX animals, a population
of the TH-immunoreactive neurons had no immunostained dendrites (Fig. 2b), although all of the
TH-positive cells exhibited long, immunostained dendrites in intact
females (Fig. 2a) and males and 10 and 30 d OVX plus
estrogen-treated females.
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Figure 1.
Light micrographs show TH-immunoreactive neurons
in the substantia nigra of female and male monkeys.
a, Intact female. b, Ten day OVX plus
2 d estrogen-treated female. c, Ten day OVX female.
d, Male. Note the higher density of TH-immunopositive
neurons in the intact female, male, and estrogen-treated OVX animals
compared with the OVX monkey. Scale bar, 500 µm.
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Table 1.
Comparative cell density analysis of the pars compacta
across groups of ovariectomized females and untreated normal males and
females of similar ages: serial section densities with SDs
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Figure 2.
Light micrographs taken from the substantia
nigra of an intact female and a 10 d OVX monkey. a,
In the intact female, all of the TH-immunoreactive neurons have long,
heavily immunostained dendrites. b, In the OVX animal,
the TH-containing cells appear to be smaller, and many of them do not
exhibit immunostained dendrites (arrows). Scale bar, 20 µm.
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To determine whether possible differences in cell size or SNpc volume
might be responsible for these changes described above, we performed
unbiased stereological calculations regarding the total volume of the
compact zone of the SNpc, the total number of neurons in this area, and
the number of TH-immunoreactive cells. These studies were
performed on six 30 d OVX monkeys; half of them received estrogen
replacement immediately after OVX, which resulted in a consistent
80-90 pg/ml serum estrogen level during the period. This analysis
showed that there was a small, but significant, change in the volume of
the SNpc between the two groups (Table 2). Furthermore, the volume
changes were in the wrong direction for them to account for the much
larger differences in cell density in the pars compacta studied in the
other experimental groups (Table 1). The total number of cells counted
was significantly reduced without estrogen replacement, but there was
no significant difference in the non-TH cells, suggesting that TH cells
were lost instead of just failing to express their TH phenotype.
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DISCUSSION |
These observations show that estrogen plays a role in maintaining
SNpc DA cells in primates and exerts a very rapid restorative action
after short-term estrogen deprivation. At 10 d after OVX, at which
time endogenous estrogen is practically eliminated, DA cell density
decreased significantly compared with that of intact females. In
addition, the data indicated that although short-term estrogen
depletion dramatically reduced the density of TH-immunoreactive SNpc
cells and dendrites (or only reduced TH below its detection level; Fig.
2), this effect was completely reversed by estrogen restoration. Two
days after estrogen replacement in these animals, the density of
TH-immunoreactive neurons recovered and was even higher than that in
intact females. In contrast, the effect of a more prolonged lack of
estrogen (30 d) cannot be reversed with short-term estrogen treatment.
Estrogen replacement for 2 d in 30 d OVX monkeys did not have
an effect, and the density of DA neurons was no different from that
seen 10 d after OVX alone. Furthermore, in the SNpc of these
animals, all of the melanosome-containing cells located in the surface
area of the sections were TH immunopositive, and putative
(melanosome-containing but TH-immunonegative) DA cells were not present.
It should be noted that the plasma levels of estrogen in the OVX
monkeys remained <15 pg/ml (which is the detection level of our assay
system), whereas during the low estrogen days of the menstrual cycle,
they are maintained at or >80 pg/ml (Hess et al., 1979). Primate DA
systems appear in general to be insensitive to native states of hormone
flux (Kritzer and Kohama, 1998). In our experiments it is most
likely that the severe and sustained reduction in estrogen levels is
responsible for the loss of TH immunoreactivity. Therefore, such
changes would probably not be normally associated with the menstrual
cycle but perhaps be more likely relevant to postmenopausal phenomena.
It appears that only a certain population of DA neurons (~40%) is
sensitive to estrogen deprivation up to 30 d, because the density
of DA cells does not decrease further between the SNpc of 10 d OVX
and that of 30 d OVX plus estrogen-treated monkeys (Table 1). This
view is supported by the observation that only a population of the TH
neurons, which may represent the estrogen-sensitive cells, appears to
lack immunopositive dendrites, whereas the other TH-immunoreactive
neurons have long, heavily immunostained processes. The dendritic loss
or the reduced TH level in these structures could be a precursor to
cell death. Experimental manipulation of the gonadal hormone levels
induces structural alterations in other brain areas. For example, the
lack of these hormones, shortly after OVX, greatly decreases pyramidal
cell spine density in the rat CA1 hippocampal subfield and can be
prevented by estrogen replacement (Woolley, 1999). However, it is not
known whether estrogen administration restores the density of spines
after a prolonged gonadal hormone deficiency.
The higher DA cell density in males compared with OVX females also
supports the view that estrogen is necessary to maintain SNpc DA cells
because males also produce a low level of estrogen as a result of
aromatization of circulating androgen (Naftolin et al., 1975).
Our data suggest that 30 d of estrogen deprivation may result in
the death of some DA neurons. Supporting this idea is the fact that
dopamine neurons usually contain melanosomes. If the reduction in the
density of TH-positive cells was caused by cells no longer expressing
TH, one would expect to see some melanosome-containing but
TH-immunonegative cells, but none were present. Second, the reduction
in the total density of neurons was almost identical to the reduction
in TH-positive neurons (although the density of non-TH neurons was not
reduced). Both of these findings would support the idea that the
neurons were no longer present (had died). However, it is possible that
the DA neurons were still present, but some were not expressing TH, and
that estrogen deprivation had led to the death of nearly exactly the
same number of other types of neurons to explain the overall reduction
in density. The finding that short-term (2 d) estrogen treatment of
30 d OVX monkeys fails to induce any recovery, as it does in
10 d OVX subjects, may suggest that this short period or the doses
of exogenous estrogen may be inadequate and that a longer or more
aggressive or complex treatment, e.g., a combination of estrogen and
progesterone, might be needed to reverse the DA cell loss. It has been
reported that hormone replacement of monkeys with estrogen alone was
less effective in reversing the OVX-induced dramatic reduction of DA
innervation of the dorsal prefrontal cortex than was a treatment
involving estrogen administration followed by progesterone
administration (Kritzer and Kohama, 1998). Therefore, especially
considering the possible consequences of any conclusions regarding DA
neuron cell death on treatment strategies in humans, further studies are needed both to characterize the mechanisms responsible for these
effects and to determine whether longer, more aggressive estrogen
treatment periods or combined estrogen and progesterone administration
will be effective in reversing the DA cell loss observed.
A number of potential mechanisms have been proposed for the
neuroprotective actions of estrogen, including the prevention of
apoptosis (see Green and Simpkins, 2000; Sawada and Shimohama, 2000).
This experiment does not answer the question of how estrogen protects
dopamine neurons. Many adverse effects on DA cells, including MPTP
treatment, induce apoptosis, and estrogen has a protective effect
against MPTP-induced neurotoxicity (Dluzen et al., 1998). Therefore, it
seems likely that the prolonged absence of estrogen induces apoptosis
in DA neurons. Whether this estrogen action on DA neurons reflects
genomic or nongenomic effects is not clear. At least in human
endothelial cells, the antiapoptotic effect of estrogen is mediated by
estrogen receptors (Spyridopoulos et al., 1998). In rodents, only a few
TH cells located in the retrorubral field contain estrogen receptor-
(Kritzer, 1997), and the presence of estrogen receptor-a was not
reported in the SN of monkeys (Blurton-Jones et al., 1999). However, a
recent study on the distribution of estrogen receptor- in rats
demonstrated the presence of this estrogen receptor subtype in a large
number of unidentified cells in ventral mesencephalic dopamine
cell-containing areas (Shughrue et al., 1997). It is also possible that
estrogen acts on DA cells indirectly, via other estrogen-sensitive
neurons. Experiments performed on cultured hippocampal cells
demonstrated that estrogen receptor-containing GABAergic interneurons
are involved in the synaptoplastic effect of estrogen on the
nonestrogen receptor-containing CA1 area pyramidal neurons (Murphy et
al., 1998). Furthermore, we have shown that estrogen
receptor-containing subcortical areas also mediate estrogenic action to
the aforementioned hippocampal neurons (Leranth et al., 2000).
Because DA cell loss during normal aging of human (Anglade et al.,
1997) and nonhuman primates (~50%) (Emborg et al., 1998) as
well as in PD (Burke and Kholodilov, 1998) is, at least partly, associated with apoptotic cell death, estrogens may play a critical role in slowing and/or preventing this process. Our findings are consistent with and help to explain epidemiological and anecdotal data,
which suggest that PD progresses more slowly in women receiving hormone
replacement therapy and that PD affects more men than women (Dluzen et
al., 1998; Saunders-Pullman et al., 1999). Furthermore, controlled
clinical studies, in which estrogen was administered to nondemented
postmenopausal women, have found that estrogen enhances memory, as it
also does in young men, and protects against memory decline (Resnick et
al., 1997; Sherwin, 1997).
In addition to its role in Parkinson's disease, the mesencephalic DA
system in conjunction with the prefrontal cortex has long-standing
links with mnemonic and cognitive tasks (Goldman-Rakic, 1998; McCarthy
et al., 1996). In subhuman primates, the prefrontal cortex receives a
relatively dense innervation of DA axons (Williams and Goldman-Rakic,
1993) that form specific synaptic triads (Goldman-Rakic et al.,
1989). DA depletion in the prefrontal cortex induced by 6-hydroxydopamine or infusion of DA antagonists in this cortical area
produces deficits in monkeys performing working-memory tasks and
disrupts performance in oculomotor-delayed response tasks, respectively
(Brozosky et al., 1979; Sawaguchi and Goldman-Rakic, 1991, 1994). In
contrast, administration of levodopa to parkinsonian MPTP-treated
monkeys ameliorates spatial memory impairments (Fernandez-Ruiz et al.,
1999). A reduced DA level in the prefrontal cortex has also been linked
to cognitive disturbances of patients suffering from schizophrenia and
Parkinson's disease, including substandard performance on frontal lobe
tasks such as the Wisconsin Card Sorting Test (Weinberger, 1987;
Goldman-Rakic, 1991). Furthermore, DA levels also dramatically decrease
in the prefrontal cortex of aged monkeys (Goldman-Rakic and Brown,
1981). Therefore, protection of these vulnerable neurons by estrogen
might be relevant to slowing down the progression of PD and preventing
the cognitive impairment in PD and/or mnemonic and cognitive
impairments associated with diseases and aging.
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FOOTNOTES |
Received March 16, 2000; revised Aug. 17, 2000; accepted Sept. 12, 2000.
This study was supported by National Institutes of Health Grants NS
36111, HD 23830, and NS 24032. D.E.R. was supported by the Research
Scientist Award MH 00643. We thank the staff at the St. Kitts
Biomedical Research Foundation for their assistance with this study,
especially O'Neal Whattley, Wellington Sutton, Sean O'Loughlin,
Ernell Nisbett, Franklyn Conner, Ricaldo Pike, and Kristin Atterbury.
We thank Dr. Michael Schwartz for helping in the statistical analyses
and Marya Shanabrough for excellent technical assistance.
Correspondence should be addressed to Dr. Csaba Leranth, Department of
Obstetrics and Gynecology, Yale University, School of Medicine, 333 Cedar Street, FMB 328, New Haven, CT 06520-8063. E-mail:
csaba.leranth{at}yale.edu.
| |
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ABSTRACT
INTRODUCTION
