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Docosahexaenoic acid reduces levodopa-induced dyskinesias in 1-methyl-4-phenyl-1 2 3 6-tetrahydropyridine monkeys.

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Docosahexaenoic Acid Reduces LevodopaInduced Dyskinesias in 1-Methyl-4-Phenyl1,2,3,6-Tetrahydropyridine Monkeys
Pershia Samadi, PhD,1 Laurent Grégoire, BSc,1 Claude Rouillard, PhD,1 Paul J. Bédard, MD, PhD,1
Thérèse Di Paolo, PhD,2 and Daniel Lévesque, PhD1
Objective: The objective of the present study was to investigate the effect of docosahexaenoic acid (DHA), a polyunsaturated fatty acid (omega-3), on levodopa-induced dyskinesias (LIDs) in parkinsonian 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)–treated monkeys. Methods: We explored the effect of DHA in two paradigms. First, a group
of MPTP monkeys was primed with levodopa for several months before introducing DHA. A second group of MPTP
monkeys (de novo) was exposed to DHA before levodopa therapy. Results: DHA administration reduced LIDs in both
paradigms without alteration of the anti-parkinsonian effect of levodopa indicating that DHA can reduce the severity or
delay the development of LIDs in a nonhuman primate model of Parkinson’s disease. Interpretation: These results
suggest that DHA can reduce the severity or delay the develoment of LIDs in a nonhuman primate model of Parkinson’s
disease. DHA may represent a new approach to improve the quality of life of Parkinson’s disease patients.
Ann Neurol 2006;59:282–288
Dopamine replacement therapy using the dopamine
precursor L-dopa remains the corner stone of Parkinson’s disease symptom treatment. Unfortunately, the
efficacy of L-dopa is seriously hampered by the fact that
a large proportion of patients develop dyskinetic involuntary movements.1 The same applies to the 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey
model in which parkinsonian syndrome and L-dopa–
induced dyskinesias (LIDs) closely match those observed in human.2,3 Once they have appeared, even if
treatment is stopped entirely for several weeks, the first
dose will still trigger the same dyskinetic behavior, indicating that treatment with L-dopa has modified the
response to dopamine and that this modification is
long lasting. The aforementioned observations therefore suggest that denervation and dopaminergic stimulation combine to elicit persistent changes in the basal
ganglia, which are consistent with an excessive or
poorly regulated response to dopaminergic agents.
Docosahexaenoic acid (DHA) is a polyunsaturated
fatty acid of the omega-3 class that is enriched in
membrane phospholipids of the brain.4 DHA is also
recognized as an endogenous activator of nuclear receptors that operate as transcription factors, such as retin-
oid X receptors (RXRs).5 Interestingly, DHA increases
the number of surviving dopaminergic cells in a process mediated by Nurr1–RXR heterodimers.6 We recently demonstrated that DHA reduced orofacial dyskinesias associated with chronic antipsychotic drug
treatment in mice.7 Similar to its role on dopamine
neuron survival, the antidyskinetic effect of DHA is
dependent on the presence of the transcription factor
Nur77, a close homologue of Nurr1, whereas a RXR
antagonist exacerbates antipsychotic-induced dyskinesias.7 Because tardive dyskinesias induced by chronic
dopamine receptor blockade with conventional antipsychotic drugs and LIDs may share common biological
substrates, we therefore undertook a series of experiments to test whether DHA may also reduce LIDs in
MPTP monkeys.
From the 1Centre de recherche en Neurosciences, Centre Hospitalier Universitaire de Québec (CHUQ), Ste-Foy, Quebec, Canada;
and Département de Médecine, Faculté de Médecine, Université Laval, and 2Laboratoire d’Endocrinologie Moléculaire et Oncologie,
CHUQ, Faculté de Pharmacie, Université Laval, Quebec City, QC,
Canada.
Published online Jan 28, 2006 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20738
Received May 26, 2005, and in revised form Sep 7. Accepted for
publication Oct 10, 2005.
282
Materials and Methods
Animals and Treatments
Handling of the primates was performed in accordance to
the National Institute of Health Guide for the Care and Use
of Laboratory Animals. All procedures, including means to
minimize discomfort, were reviewed and approved by the Institutional Animal Care Committee of Laval University.
Address correspondence to Dr Lévesque, Neuroscience Unit, RC9800, CHUL Research Center (CHUQ), 2705, Boulevard Laurier,
Ste-Foy, Quebec, Canada G1V 4G2.
E-mail: daniel.levesque@crchul.ulaval.ca
© 2006 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Cynomolgus (Macaca fascicularis) ovariectomized female
monkeys weighing 3 to 5kg were used in this study. For the
L-dopa–primed group, monkeys were exposed to the MPTP
neurotoxin until they developed a stable parkinsonian syndrome.8,9 Then, each animal was treated orally, once daily,
with L-dopa/benserazide (100/25mg, Prolopa, Hoffman-La
Roche, Missigauga, ON, Canada) during a few months, until
LIDs, with a predominantly choreic nature, developed. Dyskinesias were thereafter reproduced upon subsequent doses of
L-dopa. Before the experiments began, the monkeys received
an oral dose of L-dopa/benserazide two to three times a week
to maintain priming and for their comfort. For the first and
second experiments in L-dopa–primed group, the doses of
L-dopa (methyl ester form; Sigma-Aldrich Canada, Oakville,
ON) varied from 30 to 35mg/kg depending on the threshold
of each animal with the aim of having the maximum of dyskinesias and was always accompanied by benserazide (50mg).
DHA (100mg/kg, SC or 200mg/kg, PO; Cayman Chemical,
Ann Arbor, MI) was administered daily as a suspension in
8% PEG-600 and sterile water (pH was adjusted to 6.0 –7.0)
for the duration of the experiment, as indicated in the figures. The dose of 100mg/kg was chosen on the basis of the
effect of DHA on tardive dyskinesias and acute parkinsonism
induced by the antipsychotic haloperidol in mice.7,10 In the
first experiment with primed MPTP monkeys, we had to
stop the protocol prematurely because we denoted signs of
inflammation and infection at the sites of drug injection.
Then, in the second experiment (after several months of
washout), we used a per os route of administration for DHA.
To compensate for the eventuality of reduced absorption of
the drug due to gastrointestinal passage, we increased the
dose from 100 to 200mg/kg.
For de novo animals, MPTP-treated monkeys were first
exposed to DHA (100mg/kg, PO, in a volume of 20 to
25ml according to the weight of the animal) for 3 days before L-dopa therapy was introduced. We used a lower dose of
DHA because more chronic treatment was performed in this
experiment (several weeks instead of few days). Then, combined oral administration of L-dopa and DHA was performed on a daily basis for 1 month. In these de novo parkinsonian monkeys, a fixed high daily oral dose of 100/25
mg of L-dopa/benserazide was used in every animal.
Dyskinesias
LIDs were rated according to a behavioral scale including
abnormal movements from the face, neck, trunk, arms, and
legs, as previously described (scale: none ⫽ 0; mild ⫽ 1;
moderate ⫽ 2; severe ⫽ 3).8,9 Dyskinetic scores also included assessment of the amplitude, interference with normal
motor activity, and the frequency of abnormal movements.
For L-dopa–primed monkeys, mean dyskinetic scores were
calculated as the average of all scores obtained during 3
hours after L-dopa administration. For de novo animals, in
addition to mean dyskinetic scores, we also showed the peak
dyskinetic score, which represents the maximal dyskinetic
scores obtained for a period of 15 minutes during the “ON”
state of the animal. These nonparametric results are presented as median scores.
Parkinsonian Syndrome
The parkinsonian scores for each animal were assessed before
and after the treatments for a maximal disability score of 16,
according to a scale that we have used in several published
studies.8,9 In brief, it includes assessment of posture, mobility, climbing, gait, grooming, voicing, social interaction, and
tremor. The mean parkinsonian score has been calculated as
average of all the scores obtained every 15 minutes during 3
hours after L-dopa administration in primed MPTP monkeys
or during the “ON” state of de novo animals. These data are
presented as median scores.
Locomotor Activity
Locomotor activity was quantified using an electronic motility monitoring system (Datascience, St. Paul, MN). Using
radio wave frequency, a probe around the neck of each animal transmits the signal to a receiver fixed on each cage. This
receiver is connected to a computer and provides a motility
count every 5 minutes.
Statistical Analysis
Comparison between dyskinetic and parkinsonian scores for
L-dopa alone and L-dopa ⫹ DHA groups was performed using nonparametric Friedman’s test followed by multiple
comparisons based on Friedman rank sums for primed
MPTP monkeys and with Mann–Whitney U test for de
novo animals. For locomotor activity, total mobility counts
were compared using an analysis of variance (ANOVA) for
repeated measures followed by Fisher’s probability of least
significant difference test (PLSD). The factors described in
the Table were compared between the two groups using a
Student’s t test.
Results
The first part of the study was designed to test whether
DHA can reduce LIDs once they have appeared. We
treated a group of five MPTP monkeys with L-dopa
until persistent and stable LIDs developed, as previously described8,9 (Fig 1A, primed #1). Then, we introduced DHA (100mg/kg, SC) in combination with a
classic L-dopa treatment. The dose of DHA was chosen
on the basis of previous observations showing reduction of antipsychotic-induced tardive dyskinesias and
acute parkinsonism of this compound in mice.7,10 The
first dose of L-dopa, when reintroduced in these L-dopa–primed monkeys, produced a dyskinetic score similar to previous treatments (DOPA “pre”; see Fig 1A).
We observed a significant reduction of LIDs (approximately 35% reduction) the fourth day of concomitant
administration of DHA with L-dopa that lasted for the
duration of the combined treatment. Five days after
DHA washout, LIDs returned to their previous levels
(DOPA “post”; see Fig 1A). The addition of DHA to
L-dopa had no effect on the antiparkinsonian activity
of L-dopa and on L-dopa–induced locomotor activity
(see Fig 1A). DHA alone or its vehicle was without
effect on parkinsonian and dyskinetic scores (see Fig
1A). In the second experiment, subcutaneous injections
Samadi et al: Effects of DHA on LIDs
283
Table. Summary of the Factors That Might Alter the Development of Dyskinesias in De Novo Animals
Treatment Group
Animal No.
Weight (kg)
MPTP Dose (mg)
Time after
MPTP
(days)
Basal Parkinsonian
Score (mean score)
L-dopa
Mean ⫾ SEM
L-dopa ⫹ DHA
Mean ⫾ SEM
1
2
3
4
5
3.2
4.0
3.6
4.0
3.2
3.6 ⫾ 0.2
19.1
11.0
19.6
10.0
30.8
18.1 ⫾ 3.8
1
2
3a
4
5
3.6
3.5
3.4
3.7
4.0
3.6 ⫾ 0.1NS
22.2
16.0
12.8
7.0
11.6
13.9 ⫾ 2.5NS
390
124
71
130
30
149 ⫾ 63
150
350
200
129
123
190 ⫾ 42NS
13.7
9.2
10.0
10.0
9.0
10.5 ⫾ 0.8
12.8
13.5
12
10.1
9.7
11.6 ⫾ 0.8NS
a
This animal was removed from the experiment the first day of L-dopa treatment because it readily develops abnormal movements associated
with severe L-dopa intolerance. The data were compared between the two groups using a Student’s t test.
MPTP ⫽1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; DHA ⫽ docosahexaenoic acid; NS ⫽ not significant.
of DHA was replaced by a per os (gavage) administration (see Fig 1B, primed #2) because we denoted signs
of irritation and inflammation at the sites of injection.
The same animals, as for the first experiment, were
used after a washout period of several months. As for
the first experiment, administration of DHA (200mg/
kg, PO) with L-dopa significantly reduced LIDs (see
Fig 1B). The effect is somewhat delayed compared
with the first experiment, possibly because of the different mode of administration. However, we obtained
a similar effect on LIDs (approximately 35% reduction). In both experiments, DHA produced a constant
and global reduction of LIDs during all the period of
L-dopa effect (see time courses in Fig 2). Again, when
we stopped DHA administration (DOPA “post”),
LIDs returned to their previous levels (DOPA “pre”;
see Fig 1B). Neither antiparkinsonian effect of L-dopa,
nor the total locomotor activity of the animals, was altered by the DHA treatment (see Fig 1B).
The second part of the study was designed to test if
the addition of DHA to L-dopa can prevent or delay
the appearance of LIDs. We used 10 monkeys rendered parkinsonian with administration of MPTP, as
previously described.8,9 The two groups were matched
for factors that may alter the development of LIDs,
such as (1) MPTP doses used, (2) time necessary to
develop a stable parkinsonian syndrome, and (3) basal
parkinsonian scores (see Table). After stabilization of
their parkinsonian syndrome, half of them received
DHA (100mg/kg, PO) for 3 days, whereas the other
half received the vehicle. L-Dopa therapy then was initiated (see Materials and Methods). LIDs started to develop at the first week of treatment and increased over
time (see Fig 1C, de novo), as previously reported.8,9
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The administration of DHA with L-dopa reduced both
the mean dyskinetic score and the maximal dyskinetic
score (peak dyskinesias) induced by L-dopa treatment.
Progression of L-dopa alone and L-dopa ⫹ DHA curves
over time suggests that DHA is able to delay LID appearance and to reduce the severity of LIDs (see Figs
1C and 3). No modification of the antiparkinsonian
effect of L-dopa was observed (see Fig 1C). For the
total duration of the experiment (1 month), DHA
treatment reduced mean and maximal LID scores by
40 and 46%, respectively (see Fig 1C, insets).
The Table summarizes the factors that may have
altered the development of dyskinesias in de novo animals. These include weight, cumulative MPTP dose,
time to develop sustained parkinsonism, and basal
parkinsonian score of animals in L-dopa and L-dopa ⫹
DHA groups. There was no significant difference between the two groups of animals used in the experiment (see Table). Figure 2 displays the time course of
the development of mean dyskinesias in primed #1 and
#2 groups over time before introducing DHA treatment (DOPA pretreatment) and after different time after L-dopa ⫹ DHA combined treatment. In both experiments DHA produced a constant and global
reduction of LIDs during the effect of L-dopa (approximately 3 hours). Figure 3 shows day-to-day evolution
of the maximal dyskinetic scores in L-dopa alone and
L-dopa ⫹ DHA treated animals with de novo MPTPtreated monkeys. The cumulative LID scores obtained
after 1 month of treatment were also reduced by 60%
in the L-dopa ⫹ DHA group (see Fig 3, inset). Results
from MPTP monkeys treated with de novo L-dopa indicates that DHA may delay or prevent the appearance
of LIDs. Note that among de novo animals receiving
Fig 1. Effects of docosahexaenoic acid (DHA) on L-dopa–induced dyskinesias (LIDs) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) monkeys. (A) Concomitant administration of DHA (100mg/kg, SC) with 30 to 35mg/kg L-3,4-dihydroxyphenylalanine
methyl ester plus 50mg benserazide, SC (termed DOPA thereafter) reduces LIDs in DOPA-primed MPTP monkeys. LIDs were
scored before, during, and after DHA treatment, as indicated in the figure. The DOPA “post” measure was performed after 5 days
of DHA washout. LIDs were rated according to a scale, as previously detailed.8,9 (B) Effect of DHA (200 mg/kg, PO) on LIDs in
MPTP monkeys. DOPA-primed animals received daily DHA (orally) for 12 days in combination with their DOPA treatment. (C)
Effects of DHA on LIDs in de novo DOPA-treated MPTP monkeys. Ten animals were exposed to MPTP until they developed stable parkinsonian syndrome. Then, half of them received daily DHA (100mg/kg, PO) starting 3 days before daily oral DOPA/
benserazide (100/25mg) administration. The other half received DHA vehicle. Daily administration of DHA and DOPA was
maintained for 4 weeks. Dyskinesias were evaluated every day and averaged to obtain weekly dyskinetic scores. (insets) Average dyskinetic scores (mean and maximal) for the entire duration of the experiment (1 month) (*p ⬍ 0.05 vs DOPA group). Mean dyskinetic and parkinsonian scores were obtained from the average score for a total of 3 hours after DOPA administration in A and B
and during the “ON” state of the animal under DOPA in (C). The maximal dyskinetic scores were obtained at the dyskinetic peak
for a period of 15 minutes during the “ON” state of the animal. The horizontal line represent median score values for dyskinetic
and parkinsonian scores. The data analysis for dyskinetic and parkinsonian scores in A and B were done using nonparametric
Friedman’s test followed by multiple comparisons based on Friedman rank sums. These data were compared between the two treatment groups in C using Mann–Whitney U test. Locomotor activity is expressed as the sum of motility counts provided by the monitoring system every 5 minutes for a 3-hour period. The values were compared using analysis of variance for repeated measures followed by Fisher’s probability of least significant difference test. Total locomotor activity counts are presented as mean ⫾ SEM (N ⫽
4-5). ND ⫽ not detected.
Samadi et al: Effects of DHA on LIDs
285
Fig 2. Time courses of the development of dyskinesias after L-dopa treatment in L-dopa–primed 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) monkeys. (A) Each curve represents the average mean dyskinetic score for the first experiment with
L-dopa –primed animals (primed #1), before starting subcutaneous docosahexaenoic acid (DHA) treatment (DOPA pretreatment)
and after 2, 4, and 8 days of DOPA ⫹ DHA combined treatment (100mg/kg, SC) (N ⫽ 5, except for day 8 where N ⫽ 4). (B)
Time courses of the development of dyskinesias after L-dopa treatment in the second experiment with L-dopa–primed MPTP monkeys (primed #2). Each curve represents the average mean dyskinetic score of primed #2 animals before starting per os DHA treatment (DOPA pretreatment) and after 6, 8, 10, and 12 days of DOPA ⫹ DHA combined treatment (200mg/kg, PO; N ⫽ 5).
individual variability in the response to DHA may exist. Daily observation of the animals also indicated a
reduced level of stress in animals receiving DHA.
Fig 3. Time courses of the development of the maximum dyskinetic scores after L-dopa treatment in de novo 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys. Maximum
dyskinetic scores obtained during the “ON” state after given
treatments were daily averaged for all monkeys (N ⫽ 5 for
DOPA alone and N ⫽ 4 for DOPA ⫹ DHA group). (inset)
Cumulative maximal dyskinetic score for the total duration of
the treatment (*p ⬍ 0.05 vs DOPA alone, according to a
Mann–Whitney U comparison test). DHA was administered per
os (gavage) at a dose of 100mg/kg for a period of 1 month.
DHA, two developed almost no dyskinesias, and one
had dyskinesias of similar intensity than monkeys that
received L-dopa alone, whereas the rest of the group
had intermediate responses, suggesting that some inter-
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Discussion
Management of LIDs represents one of the most important problems encountered with classic dopamine
replacement therapy in Parkinson’s disease. The precise
biological substrate underlying the appearance of LIDs
after dopamine denervation remains obscure. Their delayed appearance and persistence after treatment cessation strongly suggest that long-term and possibly permanent basal ganglia circuitry alterations are involved.
Therefore, transcription factors, which regulate gene
expression, represent most likely candidates. Indeed,
modulation of transcription factors of the Fos family
(⌬FosB) is shown to be associated with induction of
LIDs.11,12 According to our previous observation in
the 6-hydroxydopamine-lesioned rat, we proposed that
the orphan member of the nuclear receptor family
Nur77 might also be involved.13 Considering that
Nur77 and RXRs seem to interact for modulation of
dyskinesias after dopamine antagonist treatment,7 we
may speculate that the beneficial effect of DHA on
LIDs observed in this study might result from interactions with retinoid receptors. However, other mechanisms might also be involved.14 Additional experiments
are required to address this issue.
These data suggest that DHA reduced LIDs to an extend similar to other more classic drugs (targeting neu-
rotransmitter or neuromodulator receptors) previously
tested, such as cabergoline, a long-acting D2 agonist,15
OSU6162 compound also a D2 agonist,16 BP897 a dopamine D3 partial agonist,17 and morphine.8 Amantadine is also another potential drug to reduce LIDs18,19
that gives similar (approximately 40%) LID reduction.
However, most of these compounds also reduced antiparkinsonian effect of L-dopa, caused tolerance, or displayed their antidyskinetic effects after prolonged administration. In addition, DHA produced a global
reduction of LIDs throughout the duration of L-dopa
effect, as illustrated in time courses of LID induction in
L-dopa–primed monkeys. This is similar to what we previously reported for the opioid agonist morphine.8 Note
also that our previous published experiments with
MPTP-lesioned monkeys always confirmed a high degree of denervation in animals showing parkinsonian
disability scores as shown in this study. For example,
biogenic amine levels evaluated by high-performance liquid chromatography demonstrated a decrease of dopamine concentration by approximately 90 to 95% and a
decrease of greater than 80% of the metabolites 3,4dihydroxyphenylacetic acid and homovanillic acid compared with intact monkeys in MPTP-treated animals
showing similar parkinsonian disability scores as presented here.2,20 –22 Therefore, we may safely assume that
the extent of lesions of MPTP-treated monkeys presented here should be comparable with previous studies.
Moreover, the mean parkinsonian score of animals distributed amongst the L-dopa alone and L-dopa ⫹ DHA
groups were not statistically different (see Table). The
absence of effect of DHA on antiparkinsonian property
of L-dopa is also indicative that L-dopa absorption or
brain bioavailability was not altered by administration of
this polyunsaturated fatty acid. Because L-dopa is an
amino acid derivative, the possibility that protein-rich
meal ingestion alters oral L-dopa absorption and brain
bioavailability has been documented.23,24 DHA is an essential polyunsaturated fatty acid that is rapidly taken up
by the body and rapidly incorporated into triglycerides
in the blood circulation. Although the active transport of
DHA into the brain is not well understood, strong evidence indicate that DHA easily enters into the brain.
For example, DHA has been used as a prodrug conjugate with the antipsychotic clozapine to increase the
brain-to-blood ratio of the drug. It is reported that
chemical coupling of clozapine with DHA increased the
brain-to-blood ratio of clozapine concentration by a factor of approximately 10.25
In summary, these results demonstrate that DHA
administration reduces LIDs in a nonhuman primate
model of Parkinson’s disease. If we extrapolate the dose
used in this study to humans, we obtain a range of
approximately 5 to 10g of DHA per day. This regimen
is in the range of doses reported in previous clinical
trials using DHA in the context of neuropsychiatric
disorders.26 Although these results need to be replicated in humans, it strongly suggests that an adjunct
treatment with DHA may represent a new and safe approach27 to improve the quality of life of Parkinson’s
disease patients.
This work was supported by grants from the Canadian Institutes for
Health Research (200303MOP-118040, D.L.), the Parkinson Society of Canada (D.L, C.R.), and the Parkinson’s Disease Foundation
of United States. D.L. holds a scholarship from the “Fonds de Recherche en Santé du Québec (FRSQ, D.L.).” P.S. holds a studentship from the FRSQ.
We thank S. Brochu for his excellent technical assistance.
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acid, methyl, induced, monkey, docosahexaenoic, phenyl, tetrahydropyridine, reduced, dyskinesia, levodopa
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