Parkinsons Disease

Parkinson's disease is a progressive neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Although the cause of neuronal loss is not understood, the resulting loss of motor control can be temporarily ameliorated by treatment with the dopamine precursor, L-3,4-dihydroxyphenyl-alanine (L-DOPA). However, motor fluctuations limit this therapeutic approach for most patients. Adjunctive therapy with dopamine receptor agonists with half-lives longer than that of L-DOPA may limit side effects including tremor and limb rigidity. Furthermore, dopamine agonists are now used as monotherapy in early-stage PD patients after demonstrating neuroprotective effects and reduced risk of dyskinesias.176

Other approaches that address sparing of the affected neurons would provide more long lasting and safer treatment. One theory suggests that the loss of dopa-minergic neurons in PD and other conditions such as AD and amyotrophic lateral sclerosis (ALS) is secondary to diminished levels of neurokinin peptides including substance P,177 suggesting that NK1 receptor ligands could be useful in preventing neurodegeneration. Adenosine A2a receptor antagonists have shown therapeutic benefit for dyskinesia induced by L-DOPA,178 and both A2a179 and adenosine A2a-dopamine D2 heteromers6799 have been proposed as relevant targets for this disease. As genetic studies shed new light on pathways involved in neurodegenerative diseases, additional GPCRs may emerge as targets for drugs that can halt or reverse disease progression, facilitate disease prevention, or provide more effective symptomatic relief.180

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