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

O2 O2 H2O2 OH•- 2H2OHydroxyl radical

Hydrogenperoxide

Superoxideradical

+e- +e-

+OH -2H+

+e- +e-

Natural Antioxidant mechanisms:1. In mitochondria radicals are tightly bound and reduced to

water2. 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

DA +O2 + H2O 3,4 dihydroxyphenyl acetaldehyde + NH3 + H2O2MAO

Enzymatic Oxidation of Dopamine

Auto-oxidation of DopamineDA + O2 SQ• + O2

- + H+

DA + O2- + 2H+ SQ• + H2O2

Clearance of Peroxide

2 GSH + H2O2 GSSG + 2 H2OGPOFenton Reaction

H2O2 + Fe2+ OH• + OH- + Fe3+

↓GSH

MitochondrialDamage

↑ H2O2

FREE RADICALS

CellDeathMitochondrial

Damage

Excitotoxicity ↑ Cytosolic Ca2+

Ca2+ activatedDegradative enzymes

DAFe2+

↑Free radicalProduction (?PD)

↓ Free radicalDefenses (?ALS)

ATP Ca2+

↓ATP↑ATP

Na+

Normal Conditions Energy Failure

Glutamate

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

Selegiline

Carbidopa

Tolcapone

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

EPSP

IPSP

Diazepam facilitates GABA-mediatedpresynaptic inhibition

Interneuron