54 Drug Metabolism Letters, 2012, 6, 54-59
1874-0758/12 $58.00+.00 ©2012 Bentham Science Publishers
New Insights on Dimethylaminoethanol (DMAE) Features as a Free
Gabriela Malanga1, María Belén Aguiar1, Hugo D. Martinez2 and Susana Puntarulo1,*
1Physical Chemistry-PRALIB, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Buenos Aires,
Argentina; 2Pharmaceutical Technology Department, School of Pharmacy and Biochemistry, University of Buenos
Aires-CONICET, Buenos Aires, Argentina
Abstract: Recently, a number of synthetic drugs used in a variety of therapeutic indications have been reported to have
antiaging effects. Among them, Dimethylaminoethanol (DMAE), an anologue of dietylaminoethanol, is a precursor of
choline, which in turn allows the brain to optimize the production of acetylcholine that is a primary neurotransmitter
involved in learning and memory. The data presented here includes new information on the ability of the compound to
scavenge specific free radicals, assessed by Electron Spectroscopic Resonance (EPR), to further analyze the role of
DMAE as an antioxidant. DMAE ability to directly react with hydroxyl, ascorbyl and lipid radicals was tested employing
in vitro assays, and related to the supplemented dose of the compound.
Keywords: Dimethylaminoethanol (DMAE), antioxidant, ascorbyl radical, hydroxyl radical, lipid radicals.
Recently, a number of synthetic drugs used in a variety of
therapeutic indications have been reported to have antiaging
effects. Among them, Dimethylaminoethanol (DMAE), an
anologue of dietylaminoethanol, allows the brain to optimize
learning and memory . DMAE, that is a naturally
occurring nutrient found in food such as anchovies and
sardines, is used in the treatment of panic attack, in problems
related to behavior and learning, mainly in children with
hiperactivity and attention deficit, in chronic fatigue, in light
depression syndrome, to improve the dream quality , on
periorbital oedema (swelling of the eyelids) and on skin
tightness . It was also reported that DMAE administration
to rats inhibits the formation of the aging pigment (lipofuscin)
and flushes it from the body. Lipofuscin is believed to be
formed by free radical reactions on the inefficient meta-
bolism of fatty acids, and it accumulates with age in all body
tissues. DMAE also seems to limit other aging symptoms in
brain and heart muscle . Free radical scavengers and
antioxidants can reduce lipid peroxidation and the generation
of reactive oxygen species (ROS). Live cells continuously
produce low amounts of ROS like superoxide anion (O2-)
and hydrogen peroxide (H2O2) as by-products of aerobic
metabolism. The H2O2 is further involved with transition
metals through the Fenton reaction forming highly reactive
hydroxyl radicals (•OH) . Moreover, some cellular
constituents like ascorbate (AH-) can reduce oxidized Fe3+ to
Fe2+ generating catalytically active Fe that fuels •OH and
ascorbyl radical (A•) formation. Also, unsaturated membrane
lipids can generate radical species like peroxyl (ROO•), alkoxyl
(RO•) and alkyl (R•) radicals by reactions catalyzed by Fe.
*Address correspondence to this author at the Fisicoquímica, Facultad de
Farmacia y Bioquímica, Junín 956, 1113 Buenos Aires, Argentina;
Tel: (54-11) 4964-8244; Fax: (54-11) 4508-3646;
Electron Paramagnetic Resonance (EPR), also known as
Electron Spin Resonance (ESR) is, at present, the only
analytical approach that permits the direct detection of free
radicals. This technique reports on the magnetic properties of
unpaired electrons and their molecular environment. The
electron spin resonance spectral lines have shape, width,
intensity and position (g-value), and hyperfine spectral
line splitting from the interaction of unpaired electrons
with magnetic nuclei that can determine the structure or
positions of free radical components. Biologically important
paramagnetic species include free radicals and many
transition elements. In view of the interest in the use
and characterization of natural and synthetic compounds,
the antioxidant properties of many products, including
commercially available dietary supplements from wheat
bran, gingko biloba (EGb) and alfalfa extracts [6, 7] were
compared. Therefore, EPR techniques allow the specific
identification of the antioxidant potential of a compound, or
a mix of compounds under analysis. Moreover, over the past
decade the interest in A• metabolism in biological systems
has been growing and the EPR detectable concentration of
A• has been interpreted as a reflection of the ongoing free
radical flux in the studied system . Thus, EPR techniques
might be used for the determination of free radical
generation rate and content in biological and chemical
systems, besides analyzing the capacity of a product to
scavenge an individual reactive species.
The hypothesis of this work was that the commercially
available DMAE has antioxidant properties. To analyze the
mechanisms of DMAE to exert its capacity as scavenger,
spin trapping and direct EPR spectroscopy were used to
get evidence for reduction of radical intermediates of
lipid peroxidation and hydrophilic radicals. The ability of
DMAE to inhibit rat liver microsomal NADPH-dependent
lipid peroxidation (lipid radicals), and •OH, and chemical
generation of A• radicals was studied.
New Insights on Dimethylaminoethanol (DMAE) Drug Metabolism Letters, 2012, Vol. 6, No. 1 55
MATERIALS AND METHODS
DMAE Bitartrate salt (2-dimethylaminoethanol), a
synthetic drug with therapeutic use (Fig. 1), was obtained
from Saporiti Chemical Co S.A.C.I.F.I.A., Argentina with
Analytical Certification Number 2654 (set DB 909). DMAE
is not an approved additive in the USA nor is an orphan
Fig. (1). DMAE chemical structure.
Thiobarbituric Acid Reactive Substances (TBARS)
TBARS was measured using a modified fluorescence
method . Rat liver microsomes were supplemented with
0.1 mM NADPH, 50 μM Fe-EDTA (1:2), in 100 mM
potassium phosphate buffer (pH 7.4) and incubated during
20 min at 37ºC in the presence or absence of aliquots of
DMAE. To 0.5 ml of reaction medium, 0.05 ml of 4% (w/v)
BHT and 0.2 ml of 3% (w/v) sodium dodecyl sulfate were
added. After mixing, 2 ml of 0.1 N HCl, 0.3 ml of 10% (w/v)
phosphotungstic acid, and 1 ml of 0.7% (w/v) 2-
thiobarbituric acid was added. The mixture was heated for 45
min in boiling water, and TBARS were extracted into 5 ml
of n-butanol. After a brief centrifugation, the fluorescence
of the butanol layer was measured at excit=515 nm
and emis=555 nm. The values were expressed as nmol
TBARS (malondialdehyde equivalents) per mg of protein.
Malondialdehyde standards were prepared from 1,1,3,3-
Lipid Radicals Generation Determined by EPR-spin
Rat liver microsomes were prepared in -phenyl-tert-N-
butyl-nitrone (PBN). EPR spectra were obtained at room
temperature using a Bruker Espectrometer ECS 106,
operating at 9.75 GHz with 50 kHz modulation frequency.
EPR instrument settings for the spin trapping experiments
were: microwave power, 20 mW; modulation amplitude,
1.232 G; time constant, 81.92 ms; receiver gain, 2 x 104 .
Quantitation of the spin adduct was performed using an
aqueous solution of 2,2,5,5-tetramethyl piperidine 1-oxyl
(TEMPO) introduced into the same sample cell used for spin
trapping. EPR spectra for both sample and TEMPO solutions
were recorded at exactly the same spectrometer settings and
the first derivative EPR spectra were double-integrated to
obtain the area intensity, then the concentration of spin
adduct was calculated according to Kotake et al. .
OH Production Determined by EPR-spin Trapping
Prior to use, DMPO was purified, following the method
of Green and Hill , to remove contaminants that
contribute to EPR background signal. In this procedure, 10
ml of 1 mM DMPO in doubly distilled water are mixed with
1.25 g activated charcoal for 1 min, allowed to stand for 1 h,
and then filtered. This purification procedure was repeated
twice. The basic microsomal incubation system consisted of
100 mM DMPO, microsomes (1 mg protein/ml), 0.5 mM
sodium azide, 0.6 mM DTPA, and 50 mM potassium
phosphate (pH 7.4). Reactions were started by addition of
0.5 mM NADPH. The microsomal reaction system was
transferred to a Pasteur pipette for direct observation of the
reaction in a Bruker ECS 106 EPR spectrometer at room
temperature. The EPR spectrometer settings were as follows:
microwave power, 20 mW; modulation amplitude, 0.490 G;
time constant, 655.36 ms; field scan, 100 G; scan time,
167.772 s; and modulation frequency 50 kHz .
Detection of A
A Bruker ECS 106 spectrometer was used for A•
measurements. Ascorbic acid (60 μM) in the presence of 50
μM Fe-EDTA (1:2) was supplemented with dimethylsulfoxide
(DMSO) and the spectra were immediately scanned in the
following conditions: 50 kHz field modulation, room
temperature, microwave power 10 mW, modulation
amplitude 1 G, time constant 655 ms, receiver gain 1 x 105,
microwave frequency 9.81 GHz, and scan rate 0.18 G/s .
Quantification was performed as previously described,
according to Kotake et al. .
Data in the text, figures and tables are expressed as
means ± SEM of 3 to 6 independent experiments. Statistical
tests were carried out using Statview for Windows, ANOVA,
SAS Institute Inc., version 5.0.
Peroxidation of rat liver microsomes was studied in the
presence of Fe-EDTA as the Fe catalyst and NADPH as the
reductant for the microsomal electron transfer system.
Production of TBARS exhibited a linear time course for 20-
25 min (data not shown). Supplementation of DMAE in the
concentration range of 0 to 4.2 M, did not show any
significant inhibitory effect on TBARS production by rat
liver microsomes. Since lipid peroxidation seems as the
biochemical process leading to the appearance of lipofuscin
that was reported as decreased in the tissues supplemented
with DMAE, a more sensitive and specific method, EPR,
was used to study this effect. The decomposition of hydro-
peroxides formed during NADPH-dependent peroxidation in
rat liver microsomes supplemented with Fe led to the
generation of lipid radicals, such as ROO•, RO• and R•
radicals, that combined with the spin trap PBN resulted in
adducts that gave a characteristic EPR spectrum with
hyperfine coupling constants of aN=15.8 G and aH=2.6 G
(Fig. 2A c), in agreement with computer spectral simulated
signals obtained using those parameters (Fig. 2A a). Even
though these constants could be assigned to lipid radicals,
spin trapping studies cannot readily distinguish between
ROO•, RO• and R• adducts, owing to the similarity of the
corresponding coupling constants . In the absence of
56 Drug Metabolism Letters, 2012, Vol. 6, No. 1 Malanga et al.
microsomes no EPR signal was observed (Fig. 2A b). The
addition of the tested drug exhibited a maxima scavenging
activity, reducing the PBN-adduct signal by 44% (Fig. 2A d)
in the presence of 2 M of the substance in comparison with
the control sample without the drug addition, which
represents 100% PBN-lipid radical adduct (Fig. 2A c). The
results presented here are consistent with the hypothesis that
indicates that lipid radicals are quenched by DMAE
Rat liver microsomes in the presence of DMPO, NADPH
and Fe-EDTA generate an EPR spectra (Fig. 3A c) with the
parameters characteristics of the DMPO-OH spin adduct
(aN=15 G and aH=15 G), according to computer simulation
records  (Fig. 3A a). In the absence of microsomes no
EPR signal was observed (Fig. 3A b). The basic system,
without the addition of any scavenger, which represents
100% DMPO-OH radical adduct showed an steady state
concentration of 4.5 ± 0.1 μM. The addition of the tested
Fig. (2). Scavenging ability of DMAE against lipid radicals. A. EPR spectra of the lipid radical-PBN spin adduct, (a) computer simulated
spectrum employing as spectral parameters aN=15.8 G and aH=2.6 G and g= 2.005; (b) and basal system (in the absence of microsomes); (c)
lipid radical-PBN spin adduct generated in rat liver microsomes; (d) lipid radical-PBN spin adduct generated in rat liver microsomes in the
presence of 1 M DMAE. B. Dose-dependent effect of DMAE on lipid radical content (), and percentages of inhibition shown by DMAE
supplementation on lipid radical steady state concentration ().
PBN stands for -phenyl-tert-N-butyl-nitrone.
Fig. (3). Scavenging ability of DMAE against •OH. A. EPR spectra of DMPO-OH spin adduct, (a) computer simulated spectrum employing as
spectral parameters aN=15 G and aH=15 G; (b) and basal system (in the absence of microsomes); (c) DMPO-OH spin adduct generated in rat
liver microsomes; (d) DMPO-OH spin adduct generated in rat liver microsomes in the presence of 1 M DMAE. B. Dose-dependent effect of
DMAE on •OH steady state concentration (), and percentages of inhibition by DMAE supplementation on •OH steady state concentration ().
DMPO stands for 5,5-dimethyl-1-pyrroline n-oxide.
0.0 0.5 1.0 1.5 2.0 2.5
Lipid radical (M)
0.0 0.5 1.0 1.5 2.0 2.5
Lipid radical (M)
0.0 0.2 0.4 0.6 0.8 1. 0 1.2
Hydroxyl radical (M)
0.0 0.2 0.4 0.6 0.8 1. 0 1.2
Hydroxyl radical (M)
New Insights on Dimethylaminoethanol (DMAE) Drug Metabolism Letters, 2012, Vol. 6, No. 1 57
drug exhibited a maximum in the scavenging activity,
reducing the adduct signal by 87% (Fig. 3A d) in the
presence of 2 M of the substance in comparison with the
control sample without the drug addition, which represents
100% DMPO-OH adduct (Fig. 2A c). Moreover, radical
concentration was significantly decreased as the DMAE
concentration added increased (Fig. 3B). The results
presented here are consistent with the hypothesis that
indicates that •OH was efficiently quenched by DMAE
addition, under these experimental conditions.
In Fig. (4A c) is shown the typical ESR spectrum of A•
generated in the presence of ascorbic acid and Fe-EDTA,
with the characteristic two lines at g=2.005 and aH+=1.8 G, in
accordance with computer spectral simulated signals (Fig.
4A a), obtained using the parameters stated in the Materials
and Methods section. DMSO itself was examined and no
DMSO spin adduct was observed (Fig. 4A b). A• content,
assessed by quantification of EPR signals, was significantly
decreased by the supplementation of increasing amounts of
DMAE (Fig. 4A d). The basic system which represents
100% A• content, showed a steady state concentration of A•
of (5.9 ± 0.1) 10-2 μM, which was significantly decreased by
DMAE supplementation (Fig. 4B). The results presented
here are consistent with the hypothesis that indicates that A•
was efficiently quenched by DMAE, under these experimental
The half-inhibition concentration (IC50) of DMAE, was
calculated from the respective concentration-activity curves
and represents the concentration that gives 50% of the
maximum inhibition of the microsomal lipid radical content,
the •OH production rate and the A• generation rate. The data
are summarized in Table 1. The relative scavenging capacity
(RSC) represents the number of IC50 per g of DMAE, and
would allow the comparison with the scavenger ability of
other compounds . Data in Table 1 showed the RSC for
each radical species, and strongly suggest that •OH is the
most efficiently scavenged species by DMAE among the
Table 1. The IC50 and RSC of DMAE for to the Studied
Radical Species IC50
Lipid radicals 0.4 ± 0.2 8.3
•OH 0.26 ± 0.07 41.8
A• 0.55 ± 0.06 8.3
IC50 represents the concentration that gives 50% of the maximum inhibition of the
microsomal lipid radical content, or •OH production rate, or the A• generation rate in
the chemical system.
RSC represents the number of IC50 per g of DMAE.
DMAE, that is available as a nutritional supplement, is a
chemical that have been used to treat a number of conditions
affecting the brain and the central nervous system. It has
been postulated the therapeutic use of this compound for two
major groups of pathologies: i) brain disorders, and ii) aging-
related effects. Preliminary evidence suggests that DMAE
may be helpful for attention deficit hyperactivity disorder
(ADHD) [15, 16]. Unclear results on the effectiveness of
DMAE in the treatment for either Tardive dyskinesia [15-
20], or for Huntington’s chorea disease [15, 21, 22] and
Alzheimer’s disease , have been obtained. Thus, widely
marketed as a memory and mood enhancer, and as an agent
to improve intellectual functioning, there is not complete
Fig. (4). Scavenging ability of DMAE against A•. A. Electron paramagnetic resonance (EPR) spectra from A•, (a) computer simulated
spectrum employing as spectral parameters aH=1.88 G and g=2.0054; (b) basal system (in the absence of ascorbic acid), (c) ascorbic acid 60
μM in DMSO (b); (d) ascorbic acid 60 μM in DMSO and 1 M DMAE. B. Dose-dependent effect of DMAE on A• steady state concentration
(), and percentages of inhibition by DMAE supplementation on A• steady state concentration ().
DMSO stands for dimethylsulfoxide.
Ascorbyl radical (M)
Ascorbyl radical (M)
Ascorbyl radical (M)
58 Drug Metabolism Letters, 2012, Vol. 6, No. 1 Malanga et al.
agreement among the clinical studies that support its use for
In 1954, Denham Harman proposed a free radical theory
of aging . Today a huge body of evidence confirms that
oxidative stress promotes aging and many seemingly diverse
age-associated diseases [24, 25]. In 1977, the Hungarian
physician Imre Nagy proposed the membrane hypothesis of
aging which posited the cell membrane as the key target of
free radical activity and which has been confirmed
experimentally [26-29]. Also it was shown that higher levels
of oxygen predispose membranes to produce ROS that attack
and easily oxidized the polyunsaturated fatty acids (PUFA)
in the lipid bi-layers, producing an inflammatory cascade
that causes cellular damage and senescence [30, 31].
Although aging is a natural phenomenon and bodily decay is
an inexorable process, aging can at least be postponed or
prevented by certain approaches . DMAE has powerful
anti-inflammatory effects when applied to skin, and with the
proper carrier it increases underlying muscle tone showing
acute and cumulative effects .
There is some controversy about the action mechanisms
proposed for DMAE effects [2-8, 15, 17, 33]. Moreover,
Nagy and Floyd (1984)  have shown in an in vitro study
that DMAE was a competitive •OH scavenger, supporting a
molecular mechanism for the anti-aging effects of DMAE in
terms of the membrane hypothesis of aging. More recently,
Gragnani et al.  have shown that DMAE reduced the
proliferation of fibroblasts, increased cytosolic Ca and
changed the cell cycle, causing an increase in apoptosis
(cellular death associated to free radical production) in
human fibroblasts. Thus, a basic analysis employing a
specific technique such as EPR, was employed to assess the
ability of the compound to scavenge radicals responsible for
producing damage in the water phase (such as •OH and A•)
and in the lipid phase (such as lipid radicals), comparatively.
The data presented here clearly showed that DMAE
efficiently scavenges all the radical species tested. However,
the comparison of the IC50 indicated that the efficiency is
not identical in the lipo- and hydrophilic phases. By the
direct comparison of the IC50 (Table 1) for the radical
species tested it is concluded that DMAE the best scavenger
capacity towards •OH (87% inhibition) and A• (79%
inhibition) as compared to lipid radicals (44% inhibition).
Thus, DMAE seems as a better scavenger for radicals
generated in the hydrophilic milieu, with a relative lower
ability for the scavenging of lipid radicals.
It was suggested that EGb is a scavenger of peroxyl
radicals generated in both lipid and aqueous environments
, through indirect measurements, and EPR studies .
Kose and Dogan  have shown that EGb extracts have
more antioxidant potential than water-soluble antioxidants
(ascorbic acid, glutathione and uric acid); and was as effective
as lipid-soluble antioxidants (alpha-tocopherol and retinol
acetate) in protecting red-cell suspensions against lipid
peroxidation induced by H2O2. The RSC of EGb towards
lipid radicals was 862 AU , being almost two orders of
magnitude higher than the RSC reported here for DMAE.
This observation is consistent with the lack of effect on
TBARS content in the microsomes after the addition of
DMAE, under the tested experimental conditions. The RSC
of EGb towards •OH was 260 AU , being six-fold higher
than the RSC reported here for DMAE. As EGb is a mixture
of different chemical constituents, its scavenging activity
could be due to a particular component as well as to the
interactions of different antioxidant molecules, and the
component responsible for its scavenging properties could
not be specifically identified. Further, the membrane-stabilizing
action of EGb 761 has been previously demonstrated, since it
decreased the osmotic fragility of rat erythrocytes and
penetrated into membrane phospholipid domain . Besides
Ginkgoflavone glycosides and terpenoids, the extract also
contains other substances of minor interest, such as organic
acids, which would play a role in its water solubility. Thus,
EGb extracts would be able to show both lipophilic and
hydrophilic characteristics. Moreover, Deby and Pincemail
 have suggested that polyphenolic substances in EGb
extract play a protective role at another level, since during
their transformation into quinone, they can give up two
hydrogen atoms and their electron to lipoperoxides. DMAE,
that shares with EGb the characteristic of improving brain
alert and focus , has only one hydroxyl group with
possible antioxidant ability suggesting that other mechanism
should contribute to explain the observed effects of DMAE.
However, the role of DMAE in dermatology including a
potential anti-inflammatory effect and a documented
increase in skin firmness with possible improvement in
underlying facial muscle tone  could be a conjunction of
many actions including its antioxidant activity. On the other
hand, the incorporation of chemical compounds into the cell
is a function of their lipophilicity. Thus, the antioxidant
activity of extracts appears to be dictated not only by the
structural features but also by their location in the membranes.
The small size of this molecule could be a positive factor to
get access to protect cellular targets against free radical
damage. The results presents here might be taken into
consideration for further biotechnological developments
of protective antioxidants, which could have important
applications in human diseases accompanied by free radical
injury. Any biologically active compound should appear in
the target tissues in significant amounts to elicit bioprotective
effects. Future studies should consider interactions of
the supplemented compound with endogenous antioxidants,
as well as tissue specificity, compartmentalization and
concentration levels of the active compound/s in target
organs, to appropriately assess effectiveness in vivo.
CONFLICT OF INTEREST
This study was supported by grants from the University
of Buenos Aires, and CONICET. S.P. and G.M. are career
investigator from CONICET. M.B.A. is a fellow from
BHT = Butylated hydroxytoluene
DMPO = 5,5-dimethyl-1-pyrroline n-oxide
DTPA = Diethylenetriaminepentaacetic acid
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Received: September 28, 20 11 Revised: November 29, 2011 Accepted: December 22, 20 11