Inhibitory effect of dehydroepiandrosterone on brain monoamine oxidase activity:
In vivo and in vitro studies
Iván Pérez-Neri, Sergio Montes, Camilo Ríos⁎
Department of Neurochemistry, National Institute of Neurology and Neurosurgery, Insurgentes Sur 3877, La Fama, Tlalpan, Mexico City 14269, Mexico
a b s t r a c t a r t i c l e i n f o
Received 22 April 2009
Accepted 10 September 2009
Aims: To evaluate the acute effect of dehydroepiandrosterone (DHEA) on monoamine oxidase (MAO) activity
in the corpus striatum (CS) and the nucleus accumbens (NAc) in vivo and in vitro.
Main methods: Male Wistar rats received an i.p. injection of DHEA (30, 60 and 120 mg/kg) and MAO activity
was assayed by formation of 4-hydroxyquinoline 2h later. For in vitro studies, DHEA (100nM–1 mM) was
added to brain tissue homogenates to assay MAO activity.
Key findings: DHEA significantly reduced (−24%) total MAO activity in the NAc (F=8.5, p<0.001), but not in
the CS, at 120 mg/kg dose. No significant difference was observed when MAO A and MAO B activities were
independently analyzed. When assayed in vitro, total MAO, MAO A and MAO B activities were reduced by
DHEA to 55.7, 28.2 and 54.4% in the NAc and to 71.9, 44.2 and 61.2% in the CS, respectively (IC504.7–
Significance: An inhibitory effect of DHEA on MAO activity may be involved in the antidepressant and
neuroprotective effects of the steroid. Since MAO inhibition reduces neurodegeneration in clinical trials for
Parkinson's disease, our results suggest that DHEA may be useful to treat depression and to prevent neuronal
death in this disorder.
© 2009 Published by Elsevier Inc.
Dehydroepiandrosterone (DHEA) modulates several neurotrans-
mitter systems (Pérez-Neri et al. 2008a). Some studies have focused
on the effect of DHEA on monoamine neurotransmission; however,
different results have been reported depending on the experimental
conditions tested (Catalina et al. 2001; Charalampopoulos et al. 2005;
Maayan et al. 2006).
In several brain regions, the effect of DHEA on monoamine content
and that of their metabolites has been often studied acutely (2 h after
an i.p. injection). Under those experimental conditions, it has been
reported that the steroid either increased or decreased the hypotha-
lamic dopamine content (Pham et al. 2000; Porter et al. 2005),
reduced that of norepinephrine (Pham et al. 2000) while either
increased or decreased serotonin content or that of its main
metabolite (5-hydroxyindoleacetic acid) (Gillen et al. 1999; Nguyen
et al. 1999; Pham et al. 2000; Porter et al. 2005).
Our group has previously reported that acute DHEA treatment
(30–120 mg/kg) reduced dopamine turnover in the corpus striatum
(CS), while increased that of serotonin in both the CS and the nucleus
accumbens (NAc) (Pérez-Neri et al. 2008b). Similar results have also
been reported following a chronic DHEA treatment (Maayan et al.
2006). Those studies suggest a modulatory effect of the steroid on
monoamine oxidase (MAO), the main enzyme involved in mono-
It has been reported that a chronic DHEA treatment reduced the
aging-induced (14 and 24 months) increase in total MAO activity in
the whole brain hemispheres, without altering enzyme activity in
adult (4 month old) rats (Kumar et al. 2008). Those results show that
DHEA inhibited MAO activity, but it remains to be determined if that
effect involves one or both MAO isoforms as well as if it occurs acutely
in young animals.
Two isoforms of this enzyme exist. MAO A is present in
catecholaminergic neurons and shows high affinity for norepineph-
rine and serotonin, while MAO B is present in astrocytes, interneu-
rons, and serotonergic neurons and shows high affinity for
benzylamine. Dopamine is a substrate for both MAO isoforms
(Bortolato et al. 2008; Youdim and Bakhle 2006).
MAO inhibition is relevant to neuroprotection and mood since
selective MAO B inhibitors are neuroprotective for Parkinson's disease
Amsterdam 2008; Youdim and Bakhle 2006). DHEA leads to both effects
Rabkin et al. 2006; Schmidt et al. 2005; Strous et al. 2003).
In this study, we tested if DHEA acutely modulates MAO activity
(either one or both enzyme isoforms) in young animals as well as in
Life Sciences 85 (2009) 652–656
⁎ Corresponding author. Tel.: +52 55 5606 3822; fax: +52 55 5424 0808.
E-mail address: email@example.com (C. Ríos).
0024-3205/$ – see front matter © 2009 Published by Elsevier Inc.
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brain tissue homogenates, that may shed some light to the
mechanism of action for the steroid antidepressant and neuroprotec-
Materials and methods
trans-DHEA, USP-grade propylene glycol, 4-hydroxyquinoline
(4HQ), kynuramine dihydrobromide, selegiline [R-(−)-deprenyl
hydrochloride] and clorgyline [N-methyl-N-propargyl-3-(2,4-
dichlorophenoxy)propylamine hydrochloride] were obtained from
Sigma (St. Louis, MO, USA). All other reagents were analytical grade.
Animals and treatment
and injected (30, 60 and 120 mg/kg, i.p.) to male Wistar rats weighing
200–250 g (n 6–8). Control animals received an equivalent volume of
the vehicle. Two hours after steroid administration, animals were
Directive 86/609/EEC for animal experiments, all efforts were made to
minimize animal number and suffering.
The enzyme activity assay was performed according to previous
studies (Krajl 1965; Mazzio et al. 2003; Ro et al. 2001; Samantaray
et al. 2003; Xu et al. 2005). The day of analysis, samples were thawed
and homogenized in ice-cold deionized water. Sample aliquots were
pre-incubated (37 °C, 15 min) with phosphate buffer saline (PBS
50 mM, to assay total MAO activity), selegiline (to assay MAO A
activity) or clorgyline (to assay MAO B activity) dissolved in PBS, to
1 µM final concentration.
For in vitro studies, DHEA (100nM–1 mM final concentration)
prepared in DMSO (2.5% v/v final concentration) was added to NAc or
CS homogenates without any previous treatment (n=3 independent
samples for each steroid concentration) and incubated for 5 min at
37 °C according to previous studies (Tomas-Camardiel et al. 2002). To
evaluate the effect of DMSO on MAO, another set of animals (n 5–6)
was sacrificed without treatment to dissect out the NAc and CS as
described above. Enzyme activity in the presence of DMSO was
compared to that of the same samples incubated with PBS.
The assay was started by addition of kynuramine (dissolved in
PBS) to a final concentration of 22 µM and was stopped by addition of
10% trichloroacetic acid 30 min later. Blank samples were prepared in
the same way with the only difference that trichloroacetic acid was
added before the substrate. Reaction mixtures were centrifuged at
18,500×g for 15 min, supernatants were mixed with an equivalent
volume of 1 M NaOH. Fluorescence was measured at 315 nm
excitation and 380 nm emission in a LS 50B spectrofluorometer
(Perkin Elmer, Mexico) and interpolated in a 4HQ calibration curve.
Protein concentration was determined according to Lowry et al.
(1951). Enzyme activity was expressed as nmol/mg protein/h. In vitro
results are reported as percent MAO activity considering the mean at
100 nM DHEA as 100%.
Tests for normality (Kolmogorov–Smirnov test) and homogeneity
of variance (Levene's test) were performed before other analyses.
One-way ANOVA followed by the Dunnett's test and paired Student's
t test were performed using SPSS 17.0. Non-linear regression of the
inhibition curves was performed with GraphPad Prism 5.01. Results
are expressed as mean±SEM. Significant differences were defined at
In vivo studies
DHEA treatment significantly altered total MAO activity in the NAc
(F=8.5, p<0.001), reducing this activity by 24% at the 120 mg/kg
dose (6.0±0.3) compared to the control group (7.9±0.4, p=0.002;
Fig. 1A). DHEA also altered both MAO A (Fig. 1B) and B (Fig. 1C)
activities (MAO A: F=3.4, p=0.031; MAO B: F=7.0, p=0.001), but
post hoc analyses showed that no steroid-treated group was different
from vehicle-treated animals (p>0.05).
In the CS, DHEA also altered total MAO (Fig. 1D) (F=3.1,
p=0.046) and MAO A (F=5.6, p=0.005) (Fig. 1E) activities while
a trend was found for MAO B (Fig. 1F) (F=2.4, p=0.090). However,
post hoc analyses revealed that no DHEA-treated group was
significantly different from control levels (p>0.05).
In vitro studies
The highest DHEA concentration tested (1 mM) precipitated when
added to the reaction mixture; thus, results from this concentration
represent the effect of the maximal soluble DHEA concentration
(between 100 µM and 1 mM) under our experimental conditions but
may be affected by the presence of insoluble material; no precipita-
tion was evident at the other concentration levels.
In NAc homogenates, DHEA (100 µM) reduced total MAO activity
to 55.7% (Fig. 2A). MAO A (Fig. 2B) and B activities (Fig. 2C) were
maximally inhibited, at the highest concentration tested, to 28.2 and
54.4%, respectively. The estimated IC50for DHEA on total MAO, MAO A
and MAO B activities was 11.2, 56.1 and 30.1 µM, respectively.
In the CS, DHEA inhibited total MAO activity to 71.9% at the highest
concentration tested (Fig. 2D). MAO A (Fig. 2E) and MAO B activities
(Fig. 2F) were reduced to 44.2 and 61.2%, respectively, at 100 µM
DHEA. The estimated IC50was 4.7, 14.9 and 11.44 µM for total MAO,
MAO A and MAO B activities, respectively.
In the homogenates from both brain regions, MAO activity was
apparently higher at 1 µM DHEA than that at 100nM, and also was
apparently higher at 1 mM DHEA than that at 100 µM (Fig. 2).
In a previous study, we have reported that acute DHEA treatment
(120 mg/kg) reduced dopamine turnover in the CS while increased
that of serotonin (at 60 and 120 mg/kg DHEA) in the CS and the NAc
(Pérez-Neri et al. 2008b). Monoamine turnover is dependent on
neurotransmitter release, reuptake and catabolism by MAO; thus,
among other hypotheses, a modulatory effect of the steroid on this
enzyme may be suggested. We found an acute inhibitory effect of
DHEA (120 mg/kg) on total MAO activity in the NAc (Fig. 1A). A
similar effect has been reported in the whole brain hemispheres
following a chronic treatment at a lower dose (30 mg/kg) (Kumar
et al. 2008), which showed no effect under our experimental
conditions (Fig. 1). The study by Kumar et al. (2008) showed that
DHEA inhibited the aging-induced increase in MAO activity assayed in
homogenates and synaptosomal fractions from the whole brain
hemispheres, which may suggest that the steroid led to a general
reduction in enzyme activity across brain regions. Our study extended
those results showing that the acute effect of DHEA on MAO activity is
region-dependent, leading to a significant decrease in total MAO
activity in the NAc but not in the CS, in vivo (Fig. 1).
However, our results do not rule out that the steroid inhibits
enzyme activity in other brain regions as well, leading to a significant
decrease in the brain hemispheres when analyzed as a whole. Also,
I. Pérez-Neri et al. / Life Sciences 85 (2009) 652–656
the treatment schedule [acute (present study) versus chronic (Kumar
et al. 2008)] might explain the differences between the studies. The
possible effect of DHEA on monoamine systems in other brain regions
awaits further studies.
In our in vivo studies, we found a trend towards decreased MAO A
and B activities leading to a significantly reduced total MAO activity in
the NAc (Fig. 1A–C). Since those enzyme isoforms metabolize
norepinephrine, serotonin (MAO A) and dopamine (both isoforms)
(Bortolato et al. 2008; Youdim and Bakhle 2006), our results suggest
that the steroid may modulate the metabolism of all those
monoamines in the NAc. Both MAO isoforms were slightly inhibited
by 120 mg/kg DHEA to a similar extent (Fig. 1B,C), suggesting that the
steroid may modulate them through a common mechanism.
In light of our in vivo experiments, it remained to be determined if
the steroid inhibited MAO activity through a direct interaction with
the enzyme. To address this issue, we added DHEA to brain tissue
homogenates to measure enzyme activity in vitro.
DHEA concentration-dependently inhibited both MAO A and MAO
B as well as total MAO activity in vitro at micromolar concentrations
(Fig. 2), the estimated IC50values under our experimental conditions
should be considered as preliminary due to the small sample size
included (n=3); however, they are similar to those reported for the
inhibitory effect of DHEA on glucose 6-phosphate dehydrogenase
(García-Nogales et al. 1999; Gordon et al. 1995; Won et al. 2003; Wu
1996). Also, DHEA inhibited MAO A (Fig. 2B,E) to a greater extent than
MAO B (Fig. 2C,F), which is consistent with the antidepressant effect
of the steroid, as it occurs with selective MAO A inhibitors (Bortolato
et al. 2008; Youdim and Bakhle 2006).
The apparent increase in MAO activity at 1 µM DHEA compared to
that at 100nM (Fig. 2) suggests that the steroid could increase enzyme
activityata lowerconcentration;however, due tothesmall sample size
in our experiment, this effect awaits confirmation. Also, the apparent
increase in MAO activity at 1 mM compared to that at 100 µM may be
confounded since the steroid precipitated at such high concentration.
Our results suggest that DHEA modulates both enzyme isoforms
through a direct interaction; thus, MAO activity in the CS was
inhibited in vitro (Fig. 2D–F) although there was no effect of DHEA in
vivo (Fig. 1D–F). It is possible that the steroid reaches a different
concentration in the NAc than in the CS leading to a different result on
Furthermore, since only a trend towards decreased MAO A and
MAO B activities was found in the NAc in vivo (Fig. 1B,C), it is possible
that DHEA does not accumulate to a high extent in the rat brain under
our experimental conditions. In spite of the lipophilic steroid
structure, its diffusion across the blood-brain barrier may be limited
due to its binding to plasma proteins such as albumin and sex
hormone-binding globulin. The fact that the DHEA concentration in
human cerebrospinal fluid represents only 5% of that in plasma
(Guazzo et al. 1996) supports this hypothesis.
Since the inhibitory effect of an i.p. injection of DHEA in the NAc
was observed after brain tissue homogenization for the enzyme assay,
our results suggest that the steroid–enzyme interaction remains after
cell disruption. It is still to be determined if this effect involves a
permanent modification of the enzyme.
In the present study, no significant effect of DHEA on either MAO A
or B activities was observed in vivo (Fig. 1B,C) suggesting that MAO
inhibition is not the main underlying mechanism for the effect of the
steroidon monoamine turnover as we have reported(Pérez-Neri et al.
2008b); thus, it may be due to an altered neurotransmitter reuptake
or release, although these hypotheses await further studies.
Fig. 1. Effect of DHEA on MAO activity in the NAc and CS in vivo. DHEA significantly reduced total MAO activity (A) and tended to reduce MAO A (B) and B (C) activities in the NAc. No
significant effect was found in the CS (D–F). Male Wistar rats received an i.p. injection of DHEA (30, 60 or 120 mg/kg) or an equivalent vehicle volume (n 6–8) and were sacrificed 2 h
later. MAO activity was assayed by formation of 4HQ from kynuramine. *Significantly different from control group (one-way ANOVA followed by Dunnett test).
I. Pérez-Neri et al. / Life Sciences 85 (2009) 652–656
It has been reported that DHEA inhibits dopamine uptake in vitro
(IC50 52.5 µM) (Tomas-Camardiel et al. 2002); it remains to be
determined if the steroid reaches those concentrations under our
experimental conditions. Also, DHEA may inhibit striatal dopamine
release through σ1receptor activation since selective agonists of this
receptor inhibit NMDA- and K+-stimulated dopamine release in the
CS and NAc (Ault and Werling 2000; Moison et al. 2003), and DHEA is
a sigma receptor agonist (Dubrovsky 2006; Monnet and Maurice
2006; Ueda et al. 2001).
Since MAO inhibition is neuroprotective against MPTP/MPP+
neurotoxicity(Chen etal. 2007; Mandelet al. 2005), our results suggest
that this effect may be involved in the protective effect of DHEA in
2002; Morissette et al. 2008). Other protective effects of DHEA, such as
antioxidant, antiapoptotic and antiexcitotoxic may also be involved
et al. 2007; Maninger et al. 2009; Maurice et al. 2006). The beneficial
after a single administration of the steroid (Tomas-Camardiel et al.
conditions. Actually, chronic DHEA treatment reduced total MAO
activity in the whole brain hemispheres (Kumar et al. 2008), which
may contribute to its neuroprotective effect.
Regarding the antidepressant effect of DHEA, it should also be
considered that MAO inhibitors are antidepressant drugs (Pae et al.
2007; Robinson and Amsterdam 2008) and DHEA also leads to this
effect (Rabkin et al. 2006; Schmidt et al. 2005; Strous et al. 2003).
Thus, MAO inhibition in the NAc by DHEA may be involved in its
Finally, selective MAO inhibitors are the only drugs that have
proven to be neuroprotective in clinical trials for PD (Olanow 2009),
suggesting that MAO inhibition is sufficient to reduce or delay
neurodegeneration in this disorder. Thus, inhibition of both MAO
isoforms by DHEA suggests that, along its antidepressant effect, this
steroid may be a neuroprotective approach for PD.
Fig. 2. Effect of DHEA on MAO activity in NAc and CS homogenates in vitro. DHEA inhibited total MAO activity (A,D) as well as MAO A (B,E) and MAO B (C,F) activities. NAc and CS
homogenates obtained from Male Wistar rats (n=3) without previous treatment were pre-incubated with DHEA (100nM–1 mM) for 5 min; then MAO activity was assayed by
formation of 4HQ from kynuramine.
I. Pérez-Neri et al. / Life Sciences 85 (2009) 652–656
Our results suggest that the acute effect of DHEA on MAO activity
may be involved in its antidepressant and neuroprotective effects.
This supports the hypothesis that DHEA may be a therapeutic tool to
treat depression and prevent neurodegeneration in patients with PD.
The authors wish to thank the Biomedical Science PhD program
(Institute of Biomedical Research, National Autonomous University of
Mexico). I Pérez-Neri received grants from DGEP (UNAM) and
CONACyT (186343 and 83521). S Montes receives a grant from
CONACyT (51541). Both institutions had no role in this study other
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