Considering the pre-clinical and clinical
evidence for continuous dopaminergic
stimulation (CDS)
This educational material has been supported by Abbott
Considering the pre-clinical and clinical evidence
for continuous dopaminergic stimulation (CDS)
Motor fluctuations and dyskinesias:
what have we learned from the laboratory?
<<Insert speaker’s name and affiliation>>
Learning objectives
At the end of this section you will have:
• An understanding of the animal models that have been
developed to study motor complications in Parkinson’s disease
• Greater knowledge of the mechanisms underlying motor
fluctuations and dyskinesias in Parkinson’s disease
Animal models of motor complications in
Parkinson’s disease
Model
Physiological effect
Behavioural effects
Rodent
6-OHDA lesion
(unilateral
intracerebral
injection)
Selective permanent
dopaminergic depletion
of the nigrostriatal
pathway
• Unilateral dopamine denervation causes motor
deficits in the contralateral limbs and postural
asymmetry, mimicking Parkinson’s disease
• Levodopa treatment improves these deficits but
also causes AIMs mimicking dyskinesia. In
most (but not all) rodent models, levodopainduced AIMs are accompanied by contralateral
rotation
Non-human primate
MPTP-treated
Metabolite (MPP+) is
taken up by the
dopamine transporter
and inhibits complex I of
the mitochondrial
respiratory chain
• Bradykinesia, rigidity, and postural deficits
similar to Parkinson’s disease
• Levodopa improves motor performance and
reduces disability
• Chronic intermittent levodopa treatment leads
to AIMs (dyskinesia)
AIMs = abnormal involuntary movements
6-OHDA = 6-hydroxydopamine
MPTP = 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine;
MPP = 1-methyl-4-phenylpyridinium
Adapted from: Chapter 1: The continuous dopaminergic stimulation concept and evidence to date. M Maral Mouradian. Managing Advanced
Parkinson’s Disease: The role of continuous dopaminergic stimulation. Aquilonius and Lees (Ed). 2007.
Pre-clinical studies of motor complications
Dopamine denervation is necessary for the occurrence of motor complications
Study
Finding
Papa et al, 1994
• Rats with 95% dopamine neuron loss due to 6-OHDA lesions manifest
‘wearing-off’, while rats with less severe lesions do not
Di Monte et al, 2000
• Moderate nigrostriatal denervation (60-70% striatal dopamine depletion) in
MPTP treated primates led to levodopa-induced dyskinesias; the severity of
the lesions’ enhanced sensitivity to levodopa
Winkler et al, 2002
• Intrastriatal 6-OHDA-lesioned rats exhibited a lower predisposition to
levodopa-induced dyskinesia than rats with complete bundle lesions
• Selective and partial denervation in the sensorimotor part of the striatum can
confer cellular and behavioural supersensitivity to levodopa
Paillie et al, 2007
• Levodopa given twice daily caused dyskinesias in bilateral 6-OHDA lesioned
rats
• Dyskinesia severity correlated with extent of dopamine neuron loss
increasing abruptly when neuron loss approached 75%
Papa SM, et al. Brain Res 1994;662(1-2):69-74. Di Monte DA, et al. Mov Disord 2000;15(3):459-66. Winkler C, et al. Neurobiol Dis.
2002;10(2):165-86. Paillie V, et al. Mov Disord. 2007;22(4):533-9.
Pre-clinical studies of motor complications
Pulsatile levodopa treatment is a cause of motor complications
Study
Finding
Juncos et al, 1989
• 30-day intermittent levodopa, but not continuous levodopa treatment, produced
behavioural sensitisation in 6-OHDA rats
Bibbiani et al, 2005
• Continuous apomorphine infusion improved motor function in primates for up to 6
months without dyskinesias
• Intermittent apomorphine produced dyskinesias within 7-10 days of treatment
Blanchet et al, 2001
•
•
Schmidt et al, 2008
•
•
Dyskinesias <10 days of intermittent dopaminergic treatment in MPTP-treated
primates
Only 3 of 6 primates developed dyskinesias with continuous dopaminergic
stimulation, but complications diminished in intensity
In unilateral 6-OHDA lesioned rats, pulsatile levodopa injections (1-2/day) caused
contraversive rotations and AIMs
Pulsatile (1-2/day) injections of the dopamine agonist rotigotine resulted in more
contraversive rotations than a slow release formulation
Stockwell et al, 2009
•
Continuous rotigotine delivery (via osmotic minipump) produces less dyskinesias
than pulsatile rotigotine administration (twice daily) in MPTP-treated primates
Stockwell et al, 2010
•
Switching from pulsatile levodopa or rotigotine administration to continuous
rotigotine infusion reduced the severity and duration of dyskinesias in primates
Juncos JL, et al. Ann Neurol 1989;25(5):473-8. Bibbiani F, et al. Exp Neurol 2005;192(1):73-8. Blanchet PJ, et al. Adv Neurol 2001;86:337-44.
Schmidt WJ, et al. J Neural Transmiss 2008;115(10):1385-92. Stockwell KA, et al. Exp Neurol 2009;219(2):533-42. Stockwell KA, et al. Exp
Neurol 2010;221(1):79-85.
A primate model of motor complications
Effect of continuous versus intermittent dopaminergic treatment
Reproduced from Exp Neurol 2005;192(1) Bibbiani F, et al. Continuous dopaminergic stimulation reduces risk of motor complications in
parkinsonian primates. p 73-8, Copyright (2005) with permission from Elsevier.
The development of pulsatile
levodopa-induced dyskinesias
Study background
• Unilateral 6-OHDA in the nigrostriatal fibre bundle
• Severe (> 90%) striatal dopamine denervation
• Daily levodopa injections for 2-3 weeks
• Peak-dose abnormal involuntary movements (AIMs)
Dyskinetic
[movie]
Permission kindly granted by Dr Angela Cenci-Nilsson.
Non-dyskinetic
[movie]
Potential mechanisms underlying
pulsatile levodopa-induced dyskinesias
Large peaks-and-troughs of extracellular dopamine:
• Rise and decline of levodopa and dopamine levels in the striatal extracellular fluid
correlate with the timing of AIMs
• Larger increases in striatal levodopa and dopamine in dyskinetic 6-OHDA lesioned rats
than in non-dyskinetic animals
• Chronic levodopa treatment may alter dopamine regulation and metabolism in striatum
and may lead to treatment-related adaptations
Serotonergic system:
• Treatment with serotonin autoreceptor agonists blunts the peak in extracellular
dopamine levels in dyskinetic rats
• Removal of serotonin afferents blocks levodopa-induced dyskinesias
in 6-OHDA lesioned rats
• Thus, dysregulated dopamine release from serotonergic neurons likely play a key role in
dyskinesia development
Cenci MA, Lundblad M. J Neurochem 2006;99(2):381-92. Lindgren H et al. J. Neurochem 2010;112(6):1465-76.
Carta M, et al. Brain 2007;130(7):1819-33 .
Serotonergic involvement in pulsatile
levodopa-induced motor complications
Levodopa-induced rat AIMs are abolished by dampening of serotonin neuron activity†
†
Similar study carried out in primates by Munoz et al
* = significant versus sham/vehicle
Carta M, et al. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain 2007;130(Part
7):1819-33, reproduced with permission of Oxford University Press. †Munoz A, et al. Combined 5-HT1A and 5-HT1B receptor agonists for the
treatment of L-DOPA-induced dyskinesia. Brain 2008;131(2):3380-94.
Abnormal molecular responses to levodopa
in striatal neurons in dyskinetic animals
Dyskinetic rat
Non-dyskinetic rat
ERK1/2: extracellular signalregulated kinases 1 and 2.
Phospho-ERK1/2
(15 min to 2 h
post-dosing)
Master regulator of neuronal
plasticity.
Become active when
phosphorylated on specific
amino acid.
∆FosB
(2 h to >2 weeks
post-dosing)
ERK 1/2
MSK-1
PDyn
Prodynorphin mRNA
(3 h to >2 weeks
post-dosing)
Elk1
∆FosB
Causes changes in gene
expression (via transcription
factors and histone kinases)
and changes in protein
translation (via the mTOR
pathway)
∆FosB: nuclear transcription
factor
Prodynorphin: effector gene
(codes a neurotransmitter
precursor)
Cenci MA, et al. Eur. J. Neurosci 1998;10(8):2694-2706. Andersson M, et al. J. Neurosci 2001;21(24):9930-9943. Andersson M, et al. Eur. J.
Neurosci 2003;17(3): 661-666. Westin JE et al. (2007) Biol. Psychiatry 62: 800-810. Aubert I, et al. Biol Psychiatry 2007;61:836-44. Santini E, et al.
Sci Signal 2009;21(2):ra36. (Images developed under the guidance of Dr Angela Cenci Nilsson).
Enhanced response to dopamine
Pulsatile dopaminergic stimulation leads to downstream changes in striatal dopamine neurones
Aetiology of dyskinesias: what we have
learned from the laboratory
Adapted from Thanvi B, et al. Postgrad Med J 2007;83:384-88
Aetiology of ‘wearing off’: what we have
learned from the laboratory
Nigrostriatal pathology
Reduced dopamine storage capacity
‘Wearing-off’
(also postsynaptic changes can be important)
early: several days effect
late: only hours effect of oral levodopa
Mechanisms of levodopa-induced
dyskinesia and clues to treatment
Dopaminergic
denervation
Loss of nigrostriatal
dopamine storage
capacity
Dopamine release
from serotonin
terminals
Dopamine-R
supersensitivity
Drugs acting on postsynaptic receptors and/or
signaling pathways (e.g.
mGluR5 antagonists)
Deep brain stimulation
Large intermittent
surges of extracellular
dopamine
5HT1A and
1B agonists
Abnormal signaling in
striatal D1R-rich
GABA+, Dyn+ neurons
Altered firing patterns
in GPi/SNr
Adapted from Cenci MA. Parkinsonism Relat Disord 2007;13 (Suppl 3):S263-7
Levodopa
treatment
Pulsatile drug
delivery
Microvascular
remodeling
New levodopa delivery
methods (duodenal
delivery; gene therapy)
Summary
• Pre-clinical studies have identified the potential mechanisms
involved in the development of motor complications observed in
patients with Parkinson’s disease
• In rodents and primates, the ‘wearing off’ phenomenon and
dyskinesias are apparent with intermittent dopaminergic
administration
• Basal ganglia undergo plastic changes following denervation and
long-term pulsatile dopaminergic exposure
• These changes are at least partly reversible upon switching from
pulsatile to continuous drug delivery