Dopamine-Based Approaches

The most common symptomatic therapies seek to enhance dopaminergic function to counteract PD’s hallmark pathological dopamine depletion. Existing dopamine-based therapies either increase synthesis or prevent metabolism of dopamine, or they mimic dopaminergic action in the brain through dopamine receptor agonists. Currently available therapies include Sinemet (a combination of L-DOPA, a dopamine precursor, and carbidopa, a decarboxylase inhibitor), which increases synthesis of dopamine. COMT inhibitors such as Tasmar (tolcapone) and Comtan (entacapone) block dopamine metabolism, as do MAO-B inhibitors Eldepryl (selegiline) and Azilect (rasagiline). Dopamine receptor agonists include Apokyn (apomorphine), Parlodel (bromocriptine), Permax (pergolide), Mirapex (pramipexole) and Requip (ropinirole). In addition, development of surgical therapies is underway, including cellular transplantation and gene therapy, which aim to introduce new sources of dopamine synthesis in areas of dopamine depletion. 

L-DOPA can be very effective at treating many of the motor symptoms of PD, but, over time, its effectiveness wanes and troubling side effects including dyskinesia and on-off fluctuations develop. It has been hypothesized that these side effects result from the fluctuations in plasma and brain levels of L-DOPA that occur following the ingestion of oral L-DOPA. For this reason, research has focused on providing more continuous and sustained plasma and brain levels by improving L-DOPA delivery. Approaches under investigation include duodenal delivery of L-DOPA (Antonini et al., 2008) and improved L-DOPA formulations, as well as development of L-DOPA delivery via dermal patch.

The improvement of dopamine replacement therapies is an important area of therapeutic development because they can be associated with debilitating side effects like dyskinesia.