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Treatment of
Parkinson’s Disease
Christopher Buchanan
CHEM 5398/Buynak
April 3, 2007
Parkinson’s Disease Overview
• Prevalence: 0.3% of U.S. Population
– Increases to 4-5% for those 85 years
old and older
• Dopaminergic degeneration in the
substantia nigra
– in the deep gray matter of the brain
– Basal ganglia produce less dopamine
Parkinson’s Overview (cont’d)
• Symptoms:
– Bradykinesia (slowed movements)
– Resting tremor
– Rigidity
• Other Neurotransmitters are affected
– Non-Adrenergic, Serotinergic, and Cholinergic
neurons are lost
– Results in: cognitive decline, sleep
abnormalities, depression, gastrointestinal
and genitourinary problems
– Usually Seen in Later Stages of Parkinson’s
Therapy
• Therapy should begin when normal
functions are impaired to due to
symptoms (i.e. limits daily activities)
– Therapy must be individualized based
on progression and time of onset
• Therapies vary depending on age of
onset, progression of symptoms,
and side-effects of drugs
Medicinal Therapy
• Levadopa (L-DOPA)
– Still the preferred medication to control
Motor symptoms
– Used in combination with Carbidopa to
prevent premature decarboxylation
• Drug: Sinemet
NH3+
HO
H
N
HO
NH2
HO
O
O
HO
H3C
CO2H
H
L-DOPA
Carbidopa
L-DOPA
HO
Tyrosine
H2
hydroxylase
HO
NH2
CO2H
HO
Dopa
Decarboxylase
NH2
HO
Dopamine
Levodopa
(L-DOPA)
OH
OH
HO
NHMe
• LevodopaN-methyl
is decarboxylated
to form dopamine,
transferase
thus replenishing
the dimished
supply
HO
(in Adrenal medulla)
HO
• Dopa Decarboxylase is saturated
at 70 to 100
Epinephrine
Norepinephrine
(Adrenaline)
mg/day
(Noradrenaline)
HO
NH2
-Adapted from Presentation Slide from Dr. John Buynak
L-DOPA
• Downsides
– Continual use can lead to motor
complications (dyskinesia), which must
be treated
– This can be somewhat offset by
lowering the dosage
• This is an important factor for
patients with Early Onset
Parkinson’s Disease
Dopamine Agonists
• Directly stimulate dopamine
receptors
• Bromocriptine (Perlodel)
• Pergolide (Permax)
http://en.wikipedia.org/wiki/Pergolide
wikipedia
http://en..org/wiki/Parl
odel
Dopamine Agonists
• Often used in combination with
Levadopa
• Studies have shown that its use
alone delays or lowers the incidence
of motor complications associated
with the use of Levadopa
• Often prescribed to patients with
mild disease at a younger onset age
Late Stage Parkinson’s
• Seen in 40% of Patients having received
Levadopa treatment for 5+ years
– Motor complications usually arise
• Patients experience a “wearing off” effect
– Each dose of levadopa has a shorter duration
of effect
• Motor Complications treated with:
– Dopamine Agonists, MAO-B Inhibitors, COMT
Inhibitors
MAO-B Inhibitors
• MAO = monoamine oxidase
H
R-C-NH2 + O2 + H2O
H
→
H
R-C=O + NH3 + H2O2
-Oxidative deamination
• Reduce disability and delay need for
Levadopa
– Believed to be somewhat neuroprotective
MAO-B Inhibitors
• Selegiline (Eldepryl)
http://en.wikipedia.org/wiki/Selegiline
• Rasagiline (Azilect)
http://en.wikipedia.org/wiki/Rasagiline
COMT Inhibitors
• COMT: catechol O-methyltransferase
• Inhibition increases the half life of Levadopa
--> decreases “Off” times
• Tolcapone (Tasmar):
http://en.wikipedia.org/wiki/Tolcapone
• Monitored closely due to rare side effect of
fatal hepatotoxicity
COMT & MAO Inhibitors
http://en.wikipedia.org/wiki/Image:Dopamine_degradation.svg
New Therapeutic Approaches
• Glial Cell-line-Derived Neurotrophic
Factor (GDNF)
– Shown to aid degenerating neurons
– However, there is very little evidence to
support it’s widespread use
• Adenosine Antagonists
– Colocalized with striatal dopamine (D2)
receptors
– Studies show that they often reverse
motor defects from Parkinson’s
Novel Approaches
• N-methyl-D-Aspartate (NMDA)
Receptor Antagonists
– Shown to reduce motor complications
from L-DOPA therapy
– Amantadine (Symmetrel):
http://en.wikipedia.org/wiki/Amantadine
Surgical Therapies
• Deep Brain Stimulation
– With precise brain mapping, stimulation
of the subthalamic nucleus can be
performed
– Improves motor function
– Reduces dyskinesia and need for
medications
– Downfall: often causes destructive
lesions
Interesting Observations
• An inverse relationship between
smoking and Parkinson’s has been
demonstrated
– Mechanism of protection (if any) is
unknown
• Consuming Caffeine (an adenosine
antagonist) has been linked with a
lesser risk of developing Parkinson’s
Sources
Figures: Wikipedia.org
Schapira, Anthony H., Bezard, Erwan, et. al “Novel
Pharmacological targets for the treatment of Parkinson’s
Disease.” Nature Reviews: Drug Discovery. 5 (2006): 845854.
Rao, Shobha A., Hoffman, Laura A., and Shakil, Amer.
“Parkinson’s Disease: Diagnosis and Treatment.” American
Family Physician. 74 (2006): 2046-2054
Jankovic, Joseph. “An Update on the Treatment of
Parkinson’s Disease.” Mount Sinai Journal of Medicine. 73
(2006): 682-689