Salvador Dali (Painter)

Mao Zedong (Chinese Politician) Michael J Fox (Actor)

Pope John Paul II

Muhammad Ali (Boxer)

Janet Reno (Former AG)

The Pharmacology of Parkinson’s Disease

May 22, 2014

Symptoms of PD• Resting tremor (“shaking”)- improved with

activity• Rigidity• Impaired balance• Bradykinesia (brady=slow, kinesia=motion)

– Gait disturbances– Loss of automatic movement (blinking, smiling, etc.)

• Additional symptoms:– Muscle aches, pains– Slurred speech– Cognitive (depression, anxiety, confusion)

https://www.youtube.com/watch?v=aaY3gz5tJSk

PD Age of Onset

Substantia Nigra Changes in PD

Major Circuit Important in PD

Substantia NigraCaudate

Just Add Dopamine!

But what’s the problem here?

• Not lipid soluble, can’t cross the BBB

NH3+

What about its precursor- L-DOPA?

• L-DOPA is also charged, but it crosses the BBB anyway… How?

NH3+

LAT1 transporter

L-DOPA is transported across BBB by active transport

DDC in the periphery can also convert L-Dopa to DA-still can’t cross

Current PD Therapy• Carbidopa + L-Dopa

– Peripheral DOPA decarboxylase (DDC) inhibitor

What could be some other drug targets?

Targets for Another Drug?

DA Receptor Agonists

• Apomorphine • Ropinirole

MAO Inhibitor

• Selegiline

– Retards degradation of DA– Somewhat selective inhibitor of an enzyme (MAO)

Can there be a placebo effect in treating PD?

• How might you answer that question?

STN Firing

• PD involves degeneration of the dopaminergic neurons (in the substantia nigra) that results in tremors, rigidity, and gait disturbances

• Occurs mostly in the elderly (prevalence increases with age)

• Drugs available to treat PD increase DA synthesis, prevent metabolism, or activate DA receptors

• The placebo effect is real and produces physiological changes in patients that can be measured and quantified

Major Points of Today’s Lecture

Concept Map

• Parkinson’s Disease• Dopamine• Gait disturbances• Substantia nigra• L-DOPA• BBB• DDC• Tremors• Placebo effect