The goal of this project is to develop improved pharmacotherapies for selected neurodgenerative disorder, especially Parkinson disease and Alzheimer disease. Motor fluctuations complicating levodopa therapy of advanced Parkinsons disease could not be fully explained by dietary factors or physical activity. Mounting evidence suggested that presynaptic dopamine neuron loss accounts for the appearance of wearing-off phenomena, while a steepening of the dose-response relation, a reduction in the dyskinesia threshold dose, and a narrowing of the therapeutic window for levodopa, which underly on-off responses, reflect secondary postsynaptic changes, possibly involving interactions between D-1 and D-2 dopamine receptor mediated mechanisms. Wearing-off phenomenon remitted completely and immediately with continuous dopaminomimetic therapy; on-off fluctuations gradually diminished. The ability of levodopa to reduce parkinsonian signs and to induce dyskinesias appeared to reflect distinct pharmacologic mechanisms. A new controlled release formulation surpassed all previously available oral levodopa preparation in patients with motor fluctuations. In Alzheimers disease, (3H)MK-801 binding studies suggested changes in some NMDA receptor bearing neurons. The purported NMDA receptor antagonist, dextromethorphan, failed in rats to provide neuroprotection against the endogenous excitotoxin, quinolinic acid. Doses of an M1 and M2 muscarinic receptor agonist had no effect on cognitive performance in Alzheimer patients despite attainment of central levels found active in the experimental animal. Maximally tolerated doses two alpha-2 adrenoceptor agonists also exhibited no antidementia efficacy. A synthetic somatostain agonist gained some entry in the human central nervous system, but failed to improve intellectual function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002265-12
Application #
3922512
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
1988
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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