Parkinson’s Disease and Treatment

Shalla HansonMedicinal Chemistry April 2009

Description of Disease

• Parkinson’s disease (PD) is typically considered a chronic, progressive neurodegenerative movement disorder. However, it is now known to have variety of nonmotor symptoms as well.

Major Symptoms-TRAP• Tremor• Rigidity • Akinesia/Bradykinesia• Postural InstabilityOther motor symptoms include:• Gait• Dystonia• Hypophonia• Drooling• Dysphagia• Fatigue • Akathesia

Nonmotor Symptoms• Mood—20-80% suffer from depression.• Behavior—indirectly, e.g., a result of dementia, depression.• Thinking-slowed reaction time and executive dysfunction• Sensation—impaired sense of smell• Excessive daytime sleep, insomnia, and REM sleep

disturbances.• Vision problems• Impaired proprioception• Oily skin• Weight loss• Incontinence• Constipation• Drooling

Primary Known Causes

• Idiopathic—majority of cases• Genetic• Drug induced—Calcium Channel Blockers• Toxins—Supported by the geographically

varied incidence• Head Trauma• Cerebral Anoxia

Pathophysiology

• Decreased stimulation of the motor cortex by the basal ganglia, usually due to the inadequate production and action of dopamine (produced in the dopaminergic neurons of the brain.)

• The specific region affected seems to be the pars compacta in the substantia nigra where there is a marked loss in dopaminergic cells.

• We also see a considerably high activity in the cells of the Subthalamic nucleus, which inhibits movement.

• High presence of Lewy bodies in dopaminergic cells.

Diagnosis

• PET Scan—decreased dopaminergic activity in the substantia nigra

• Unified Parkinsons Disease Rating Scale—cognitive interview

• Normal CT• Normal MRI

History• PD was first described in detail by James Parkinson in 1817

in “An Essay on the Shaking Palsey.”• Carlsson in 1950, determined that dopamine was a

neurotransmitter and was exceptionally concentrated in the basal ganglia.

• Carlsson’s research later showed that Reserpine demonstrates a correlation between motor impairment and decreased dopamine levels. L-Dopa also given to animals which alleviated symptoms and initiated medicinal therapies for PD in 1967.

• In California in 1980 a group of opiate addicts consumed MPTP N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and revealed a pro-toxin, allowing another animal model of PD.

Treatment

• Education• Exercise• Nutrition• Psychiatric counseling

Treatment

• Oral Medication– L-Dopa (aka Levodopa)– Most popular treatment– Form of dopamine which

is able to cross the BBB through transport in L-AA system and can then be metabolized to dopamine.

– Sinemet = levodopa + carbidopa

Treatment• Oral Medications– MAO-B Inhibitors– Selegiline = most common

• Dopamine Agonists– Ropinirole– Apomorphine– Lisuride

• COMT Inhibitors (Catachol-O-methyl transferase Inh.)– Tolcapone– Entacapone– Stalevo = levodopa, carbadopa, and entacapone

Treatment

• Surgical Procedures – Deep Brain

Stimulation – Creating a lesion in

the subthalamic nucleus or globus pallidus

Current Research

• Gene Therapy– GAD = Glutamic Acid Decarboxylase

• Deep Brain Stimulation– Controlled Impulses– Pallidotomy-not enough data to assess results well– Subthalotomy—improvements in contralateral rigidity– Subthalamic Deep Brain Stimulation—mimics

Levodopa

Works CitedBritton, Thomas C. "NONMOTOR ASPECTS OF PARKINSON'S DISEASE."

Current Medical Literature: Neurology 20 (2004): 45-50."Parkinson's Disease." Current Medical Literature: Neurology 23

(2007): 44-48.Marceglia, Sara, and Alberto Priori. "Sex, genes, hormones and nigral

neurodegeneration: two different Parkinson's diseases in males and in females." Future Neurology 2 (2007): 499-503.

"Literature Review: Pathophysiology." Current Medical Literature: Parkinson's Disease 5 (2003): 59-61.

"Literature Review: Medical Treatment." Current Medical Literature: Parkinson's Disease 5 (2003): 66-70.

"Literature Review: Surgical Treatment." Current Medical Literature: Parkinson's Disease 5 (2003): 71-72.