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Levodopa-induced dyskinesias improved by a glutamate antagonist in parkinsonia monkeys.

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ORIGINAL ARTICLES
Levodopa-induced Qskinesias Improved bY a
Glutamate An.ta.gonist in Parhsonian
Monkevs
J
Stella M. Papa, MD, and Thomas N. Chase, MD
~
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~~~~
Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor have been reported to potentiate the
antiparkinsonian action of levodopa and reverse levodopa-induced motor fluctuations in animal models of Parkinson’s
disease. To evalute the effect of NMDA receptor blockade on dyskinesias complicating the response to long-term levodopa therapy, we studied the selective antagonist LY235959 in six l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. Drugs were administered subcutaneously, LY235959 at doses of 0.5, 1.0, 3.0, and 5.0 mglkg and
levodopa/benserazide at doses that produced moderate dyskinesias while almost totally reversing parkinsonian signs.
Compared with vehicle control injections, LY235959 (3.0 mg/kg) abolished oral dyskinesias and diminished choreic
dyskinesias by 68% ( p < 0.01). Lower doses had smaller effects, although still significant, on oral dyskinesias (55%
reduction at 1.0 mg/kg, p < 0.05). The highest LY235959 dose (5.0 mg/kg) prolonged oral dyskinesia suppression,
but tended to increase dystonia severity. LY235959 had no effect on motor function when given alone and did not
reduce the antiparkinsonian response to levodopa. These findings suggest that NMDA receptor blockade may ameliorate
the dyskinetic complications of long-term levodopa therapy, without diminishing the beneficial effects on parkinsonian
signs.
Papa SM, Chase TM. Levodopa-induced dyskinesias improved by a glutamate
antagonist in parkinsonian monkeys. Ann Neurol 1796;39:574-578
The pathogenesis of the alterations in motor response
that complicate levodopa therapy of Parkinson’s disease
remains obscure [ 11. Although motor fluctuations of
the wearing-off type have been presumed to reflect the
decline in vesicular dopamine storage as a consequence
of the progressive degeneration of nigrostriatal dopaminergic projections, more recent evidence suggests
that secondary changes in basal ganglionic pathways
downstream from the dopamine system contribute to
the exacerbation of wearing-off phenomenon as well as
to the ultimate appearance of on-off fluctuations and
peak-dose dyskinesias [2].
The chronic administration of levodopa to parkinsonian rats profoundly affects transmitter systems within
the basal ganglia as well as motor function [3-51. At
the same time, these animals exhibit modified responses to levodopa reminiscent of the wearing-off and
on-off fluctuations that occur in levotiopa-treated parkinsonian patients [GI. Recent observations suggest
that the motor response alterations induced by levodopa might reflect upregulation of certain glutamate
receptor-mediated responses. T h e basal gangliaare richly
innervated by glutamate-containing neurons, including
projections from the cerebral cortex to the corpus striatum and subthalamic nucleus as well as from the subthalamic nucleus to the internal segment of the globus
pallidus [7].Thus it is hardly surprising that drugs
known to interact selectively with glutamatergic subsystems can influence motor function [8]. Antagonists of
the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, for example, potentiate the effects of
levodopa in both rodent and primate models of Parkinson’s disease [9, 101. Very recently, we found that
levodopa-induced alterations in the dopaminergic responses in “direct” striatonigral and “indirect” striatopallidal pathways as well as the associated levodopainduced motor fluctuations can be reversed in rats by
systemic administration of the NMDA antagonist MK801 [ l l ] .
The foregoing results suggest that drugs that interfere with NMDA-mediated glutamatergic transmission
could exert an amelioratory effect on certain complica-
From the Experimental Therapeutics Branch, National Insrirute of
Neurological Disorders and Stroke, National linsririites of Health,
Bethesda, MD.
Address correspondence to Dr Chase, Experimental Therapeutics
Branch, NINDS, Building 10, Room 5C103, 3000 RockviIle Pike,
Berhesda, MD 20892.
Received Sep 21, 1335, and in revised form llec 6. Accepted for
publicacion Dec 11, 1995.
574 Copyright 0 1976 by the American Neurological Association
tions of the levodopa response. To determine whether
this possibility extends to include dyskinesias as well
as to elucidate the pathogenesis of the altered motor
responses to levodopa, we studied the ability of a highly
selective NMDA receptor antagonist, LY235959 [ 121,
to mitigate levodopa-induced involuntary movements
and abnormal postures in 1-methyl-4-phenyl- 1,2,3,6tetrahydropyridine (MPTP)-lesioned monkeys.
Materials and Methods
Subject Preparation
Six adult monkeys (3 male and 3 female; 3 Macaca mulatta
and 3 fascicularis) were housed and studied in accordance
with the National Institutes of Health (NIH) Guidefor the
Care and Use of Laboratory Animals. All had been intravenously injected with MPTP 6 to 12 months prior to experimental drug treatment. MPTP was administered weekly
(0.5-1.0 mglkg) for 1 to 6 months until stable parkinsonism
developed (cumulative MPTP dose ranged from 1.25-10.50
mgikg). Three to 5 weeks after the last MPTP injection,
antiparkinsonian treatment was initiated. Subsequently, each
monkey was given levodopa/carbidopa (Sinemet 25/ 100 mg)
orally two or three times daily at the minimal dose (25-75
mg) that produced an adequate antiparkinsonian response.
Within 1 to 4 months, every animal evidenced levodopainduced dyskinesias.
Drug Administration
On study days, each animal received either vehicle or one
of four doses of the competitive NMDA receptor antagonist
LY235959 (the active isomer of LY274614, Eli Lilly, Indianapolis, IN), 5 minutes before the administration of levodopa. LY235959 was dissolved in distilled water and injected
subcutaneously at doses of 0.5, 1.0, 3.0, and 5.0 mglkg.
Vehicle and each LY235959 dose were tested three times in
random order at intervals of at least 24 hours. Levodopa
methyl ester (Sigma Chemical, St. Louis, MO) plus the peripheral decarboxylase inhibitor benserazide (Hoffmann-La
Roche, Nutley, NJ) were dissolved in saline solution and
given subcutaneously at the lowest dose (100/25, 150/37.5,
or 200/50 mg) for each monkey that induced moderately
severe dyskinesias while producing nearly total suppression
of parkinsonian signs. The effect of LY235959 (3.0 mg/kg)
alone on motor function was evaluated once in each animal
24 hours afier withdrawal of their regular levodopa treatment.
Motor Assessments
Monkeys, placed in individual cages, were scored before drug
injection and every 20 minutes thereafter for 4 hours. They
were also simultaneously videotaped for subsequent blinded
scoring by other investigators. A play cage (1.7 X 1.0 X 2.3
m) served to evaluate walking and climbing in the presence
of dyskinesias. Motor behavior was scored on a disability
scale developed for MPTP-treated monkeys:
posture: N (normal) = 0, flexed = I ,
crouched = 2; gait: N = 0 , slow = 1, freezing = 2; tremor:
absent = 0 , mild (present only in some postures) = I , severe
PARKINSON SCORE.
(present in most postures) = 2; general mobility: N = 0 ,
reduced (moves spontaneously but less than normal) = 1,
very reduced (moves spontaneously but stays longer in the
same position, usually seated) = 2, inapparent (moves actively only by stimulation, defensive response) = 3; absent = 4; hand movements: N = 0 , slow = 1, very slow
(failure to catch) = 2; climbing; N = 0 , reduced (less frequent) = 1, difficult (less frequent and slow) = 2, unskilled
(slow and freezing) = 3, incapable = 4; holding food:
capable = 0, incapable = 1; eating: present = 0 , absent =
1; social interactions: N (includes ability to jump in reaction
to attack) = 0, hyporeactive = 1, absent = 2. Scale range
is 0 to 20.
Neck, trunk, fdce, and limbs
rated separately: absent = 0, mild = 1, moderate = 2, severe
= 3. Scale range is O to 21.
CHVREIC DYSKINESIA SCORE.
Neck, trunk, file, and
limbs rated separately: absent = 0, mild = 1, moderate =
DYSTONIC DYSKINESIA SCORE.
2, severe = 3. Scale range is 0 to 21.
ORAL DYSKINESIA SCORE. Absent = 0, mild =
ate = 2, severe = 3. Scale range is 0 to 3.
I , moder-
In addition, stereotypies, turning, hyperactivity, bizarre
behaviors, somnolence, and vomiting were each evaluated
qualitatively.
Statistical Analysis
Data are presented as group mean 2 standard error of mean
scores for three consecutive 20-minute intervals for three
control and three LY235959 injections at each dose. Twofactor repeated-measures analysis of variance (ANOVA) followed by the post hoc Dunnett t test, when the ANOVA
indicated significance, was employed to compare LY235959
with vehicle control treatment.
Results
Antiparkinsonian Efects
Levodopa alone reduced the severity of parkinsonian
signs by 97% at the time of its peak effect during the
hour following administration (Table). Subsequently,
parkinsonism began to gradually worsen, with scores
returning to baseline values 4 hours after levodopa injection.
LY235959 alone (3.0 mg/kg) had no effect o n parkinsonian severity (parkinsonian scores of 12.8 ? 1.0
and 12.8 t 1.0 at baseline and 1 to 4 hours after injection). Moreover, LY235959, at doses of 0.5, 1.0,
and 3.0 mg/kg, did not decrease the antiparhnsonian response to levodopa (see Table), which was
given to each animal in an amount that produced an
essentially maximal response. At 5.0 mg/kg, however,
LY235959 increased parkinsonian scores due to an increase in dystonic dyskinesias that worsened gait and
climbing.
Papa and Chase: Glutamate Antagonists in Parkinson’s Disease
575
Effect of LY235959 on the Antiparkinsonian Response to Levodopaa
Hours after Treatment
LY235959
Dose (rng/kg)
Baseline
0
0.5
1.0
3.0
5.0
12.8
12.8
12.8
12.8
12.6
5 1
0.4
0.3
0.3
0.5
2.1
i1
? 1
? 1
i1
3
2
1
i .2
i .2
I
.2
-t .2
2 .8h
2.4
2.8
3.2
2.7
4.2
4
8.6
10.7
10.6
10.3
10.8
i1
& 1
& 1
2 1
I
1
22
i1
? 2
? 2
5 2
12.8
12.8
12.8
12.8
12.6
i1
? 1
? 1
? 1
? 1
'LY235959 or vehicle was given 5 minutes before Ievodopalcarbidopa. Parkinsonian scores were determined immediately before treatment
and every 20 minutes following drug adminisrration. Values (mean t SEM) are an average from three consecutive 20-minute evaluations.
hp< 0.01 for difference from levodopa plus vehicle control.
- -.D-
..
--t-
L-Dopa + Vehicle
- - -D. - - L-Dopa + Vehicle
2
L-Dopa + LY235959 0.5 m g k g
rl
I \
II
\ \
p,
I
I
--c
L-Dopa + LY235959 1 m g k g
--it--
LDopa + LY235959 3 m g k g
,
;
>
\
I<
1.5
'\\
V
A
\ I
I
--c
m
L-Dopa + LY235959 0.5 mgfkg
L-Dopa+LY235959 I mgkg
L-Dopa + LY235959 3 mgkg
L-Dopa + LY23.5959 5 r n g k g
.-m
v1
.-e
1
1
B
m
0.5
0
0
I
,
I
,
I
0
1
2
3
4
Hour
Dyskinetic Efects
Levodopa/carbidopa treatment
produced choreiform dyskinesias in 4 monkeys, mainly
affecting the lower extremities. LY235959, at a dose of
3.0 mg/kg, diminished chorea in these animals by 68%
during the first 2 hours following levodopa administration ( p < 0.01 and 0.05; Fig 1). Both lower arid higher
doses of the NMDA antagonist led to smaller and statistically insignificant changes in levodopa-induced
chorea (see Fig 1).
CHOREIC DYSKINESIAS.
ORAL DYSKINESIAS. Three animals manifested oral
dyskinesias characterized by virtually continuous movements of the mouth and tongue. At 1.0 mg/kg,
Vol 39
2
3
4
Hour
Fig 2. Effect of LY235959 on oral 4Iskinesias induced by
Fig 1. Effect of LY23.5959on choreic dyskinesias induced by
levodopa. Each data point represents mean scores fiom 4 monkeys (error bars were omitted f o r clarity). Hour 0 indicates
the baseline score obtained just before drug injections "p <
0.01 and fp < 0.05 for diference betwcen levodopa plus
LY235959 and levodopa plus vehicle control.
576 Annals of Neurology
1
No 5 May 1996
levodopa. Each data point represents mean scores fiom 3 monkeys. Hour 0 indicates the baseline score obtained just befire
drag injections. *p < 0.01 and f p < 0.OSfor difference
between levodopa plus LY235959 and levodopa plus vehicle
control.
LY235959 reduced oral dyskinesias by 55% ( p < 0.05;
Fig 2). When given at 3.0 or 5.0 mglkg, LY235959
completely suppressed oral dyskinesias during the first
hour after treatment ( p < 0.01). The higher dose had
a more prolonged effect, which lasted 2 hours ( p <
0.05; see Fig 2).
DYSTONIC DYSKINESIAS. In 3 animals dystonic dyskinesias also developed in response to levodopa. These
dystonic movements and postures, primarily involving
the lower limbs, trunk, and neck, were unaffected by
LY235959 at the 0 . 5 , I.O-, and 3.0-mg/kg doses
(Fig 3). At 5.0 mg/kg, LY235959 substantially increased dystonia in 2 animals, although for the entire
group of 3 dystonic animals this change did not attain
statistical significance (see Fig 3 ) .
8
i n---o---
L-Dopa + Vehicle
--+-
L-Dopa + LY235959 0.5 m g k g
-a+-
L-Dopa + LY235959 1 mgkg
L-Dopa + LY235959 3 mgkg
I
I
I
I
I
0
1
2
3
4
Hour
Fig 3. Effect of ~Y235959on dystonic dyskinesias induced by
levodopa. Each data point represents mean scores from 3 monktys. Hour 0 indicates the baseline score obtained just before
drug injections. None of the diferences between levodopa plus
LY235959 and levodopa plus vehicle control treatments were
statistically signijicant.
Some animals showed
mild hyperactivity, turning, and bizarre behaviors in
response to levodopa. These were unaffected by the
addition of LY235959. Given alone, LY235959 did
not induce abnormal behaviors or other clinically observable adverse effects.
OTHER ABNORMAL BEHAVIORS.
Discussion
Systemic administration of LY235959 to levodopatreated parkinsonian monkeys, at doses that did not
reduce their antiparkinsonian response, substantially
reduced choreic dyskinesias and abolished oral dyskinesias. Although putative NMDA receptor antagonists
can potentiate the therapeutic response to levodopa in
various animal models of this disorder [9, lo], this is
the first report of an ameliorative effect on levodopainduced dyslunesias. The present results thus extend
earlier findings that NMDA antagonists diminish motor fluctuations, the characteristic response modification in levodopa-treated parkinsonian rats [G,131. The
lack of any effect of LY235959 monotherapy on parkinsonian signs contrasts with the reported activity of
some, but not all, NMDA antagonists [lo] and could
reflect the administration of insufficient LY235959
doses or differences in NMDA receptor subtype binding profile. A potentiating action of this drug on the
antiparkinsonian response to levodopa could not be
readily assessed in this study owing to our use of su-
praoptimal amounts of the dopamine precursor in order to evaluate the effects of an NMDA antagonist on
levodopa-induced dyskinesias. In agreement with an earlier report [14],LY235959 not only failed to diminish
levodopa-induced dystonia but actually exacerbated dystonia in 2 of the 3 animals manifesting this complication,
possibly indicating that transmitter mechanisms for dystonic dyskinesias differ from those mediating chorea.
The present observations suggest that NMDA receptor
blockade can attenuate the dyskinesias associated with
chronic levodopa therapy in parkinsonian primates.
LY235959 is a highly selective NMDA antagonist [12],
whose optimal dose in this study appeared to be about 3.0
mgl kg. Higher doses generally had no further beneficial
effect or tended to increase dystonic dyskinesias. This “inverted U-shaped” dose-response relation could reflect an
interaction at high doses with additional NMDA receptors that influence motor function. The type and distribution of NMDA receptor subtypes that mediate the antidyskinetic effects of LY235959 are unknown. In
parkinsonian rats, the NMDA antagonist MK-801 reduces motor fluctuations by acting primarily in the striatum [ 131. Convergence of cortical glutamatergic and nigral dopaminergic afferents on the dendritic shafts and
spines of individual striatal medium spiny neurons provides an anatomical basis for a functional interaction between these systems [ 151. The animal model data, taken
together, may thus indicate that upregulation of NMDA
receptor-mediated mechanisms within the medium
spiny neurons as a consequence of chronic levodopa therapy contributes to the appearance of motor response complications.
The possibility that NMDA receptor blockade will
improve the therapeutic index of levodopa could have
important implications for patients with advanced Parkinson’s disease. Motor response complications eventually constitute a major source of disability for these
individuals. One experimental approach to this problem has been to surgically ablate the internal segment
of the globus pallidus. The ability of this procedure to
reduce contralateral dyskinesias [ 161 has been attributed to the interruption of glutamatergic projections
from the subthalamic nucleus [ 171. If true, an alternative strategey might be to block portions of the glutamate system pharmacologically. Further evaluation of
this approach, now supported by preliminary clinical
evidence [18], will depend on the discovery of more
effective NMDA antagonists suitable for human administration. In view of the potential importance of
this drug class for not only the palliative but also the
protective treatment of Parkinson’s disease [I 91, the
recent discovery that multiple NMDA receptor subunits exist, with regional and cellular specificity as well
as functional and pharmacological diversity [2O], will
undoubtedly stimulate this developmental effort.
Papa and Chase: Glutamate Antagonists in Parkinson’s Disease
577
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1-16
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