Parkinson’s Disease

• Resting tremor, bradykinesia, rigidity. Loss

of postural reflexes. Death due to
complications of immobility.
• Degeneration of dopaminergic neurons of
the nigro-striatal pathway. Decrease in
dopamine content of the
• Imbalance between dopaminergic and
cholinergic innervation in the striatum.
 Pathophysiology of Parkinson’s Disease
Increased production of free radicals (reactive oxygen species)
and deficiency of antioxidant mechanisms
+e- +e- +e- +e-

O2 O2
- H2O2 OH• OH +
- 2H2O
+
2H
Superoxide Hydrogen Hydroxyl
radical peroxide radical

Natural Antioxidant mechanisms:

1. In mitochondria radicals are tightly bound and reduced to
water
2. O2- dismutated by SOD to H2O2 and then cleared by catalase
or glutathione peroxidase
3. Free radical scavengers (vit. E, ascorbate) which can react
directly with free radicals
Evidence for Free Radical Hypothesis

• Polyunsaturated fats major constituent and

substrate for lipid peroxidation → free radicals
• Free Fe++ level high in S. nigra –promotes radical
formation
• Fe++ binding capacity is limited in brain
• Brain contains almost no catalase, and low levels
of glutathione, glutathione peroxidase and vit. E
• Oxidative metabolism of dopamine potential to
generate radicals
 Dopamine Metabolism
Enzymatic Oxidation of Dopamine
DA +O2 + H2O 3,4 dihydroxyphenyl acetaldehyde + NH3 + H2O2
MAO
Auto-oxidation of Dopamine
DA + O2 SQ• + O2- + H+
DA + O2- + 2H+ SQ• + H2O2

Clearance of Peroxide
2 GSH + H2O2 GSSG + 2 H2O
GPO
Fenton Reaction
H2O2 + Fe2+ OH• + OH- + Fe3+
 ↓GSH

Mitochondrial ↑ H2O2 Fe2

+
DA
Damage

Free radical ↓ FREE RADICALS Free radical ↑

Defenses (?ALS) Production (?PD)

Cell Ca2+ activated

Mitochondrial Death
Damage Degradative enzymes

Excitotoxicity Cytosolic Ca2 ↑

+
 Glutamate

+
Na
ATP +Ca2

ATP↑ ATP↓

Normal Conditions Energy Failure

Treatment of Parkinson’s Disease
• Levodopa: Dopamine precursor
Levodopa + Carbidopa (Sinemet®)
• Selegiline: MAO-B selective inhibitor
• Amantadine: ↑ Dopamine release (also antiviral)
• Dopamine receptor agonists: bromocriptine,
pergolide, lisuride
• Tolcapone: COMT Inhibitor
• Trihexphenidyl: anticholinergic
• Surgery: fetal transplants.
 L-Dopa Carbidopa

Tolcapone Selegiline
 Adverse effects of L-Dopa
• Nausea and vomiting
• Tachycardia, increased contractility,
arrhythmias
• Orthostatic hypotension
• Dyskinesias
• Behavioral disturbances (hallucinations,
paranoia, mania, insomnia, anxiety,
nightmares)
 Late Complications of L-Dopa
• Wearing Off and On-Off Phenomena
• Pharmacokinetic explanation
• Pharmacodynamic explanation
• Strategies to manage:
– Infusion, sustained release, or multiple short
interval doses of L-Dopa
– Add selegiline to prevent metabolism
– Use receptor agonists
 Other Drugs
Selegiline
• Blocks MAO-B (found in CNS) not MAO-A also found in
periphery
• Provides symptomatic benefit and/or slows progression of
the disease.
• Of limited value in advanced disease
Trihexphenidyl
• Additive effect to others at any stage of the disease
• All symptoms relieved but less effective than L-Dopa
• Anticholinergic side effects
 Dopamine receptor agonists
• Especially useful in advanced stages of PD
• Bromocriptine: D1, Pergolide: D1 & D2 agonists
• In general less effective than L-Dopa
• Same pattern of adverse effects as L-Dopa. First
dose phenomenon: sudden cardiovascular collapse
• Bromocriptine: Inflammatory pleuropulmonary
reactions and fibrosis
• Bromocriptine also used in the treatment of
hyperprolactinemia and acromegaly
 Drugs for Spasticity
• Baclofen: derivative of GABA activates GABA-B
receptors. Acts in spinal cord at presynaptic terminals to
inhibit motoneuron firing by decreasing release of
excitatory neurotransmitter.
• Mechanism: hyperpolarization by ↑ K+ conductance and
inhibition of Ca++ channels.
• Drowsiness, insomnia, ataxia, confusion. In overdose:
coma, respiratory depression and seizures.
• Benzodiazepines.
• Dantrolene: acts on muscle. Generalized muscle weakness.
• Others: Clonidine, botulinum toxin.
 Baclofen interferes
with release of
excitatory transmitters

Diazepam facilitates
GABA-mediated
presynaptic inhibition
Interneuron

EPSP

IPSP