Parkinson’s Disease and Treatment
Shalla Hanson Medicinal 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 Instability Other 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 Cited
Britton, 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.