Parkinsons Disease and Treatment Shalla Hanson Medicinal Chemistry

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.