Update on the Present and Future Pharmacologic Treatment of Parkinson's Disease.

Symptomatic drug treatment of Parkinson's disease combines various pharmacological principles for a patient-tailored drug combination. Development of more continuous delivery modes of dopamine-substituting drugs with formulations with better pharmacokinetic properties has enabled less frequent dosing and thereby provided further benefit for patients. Peripheral weakening of dopa decarboxylase activity with nutrients, such as short fatty acids, may enhance levodopa efficacy. A future concept may be mandatory combined central inhibition of catechol-O-methyltransferase, monoamine oxidase B and tyrosinase in levodopa-treated patients, if tolerated. This approach may hypothetically protect against toxins resulting from catecholamine metabolism. Beneficial modification of disease progression and cure is an unmet need. High expectations were mainly generated by promising positive experimental research outcomes. The employed models of Parkinson's disease provide uniform trial conditions. Drug safety and the side effect profile have minor importance. Subsequently performed translational clinical trials failed. Examples are studies with iron chelators, glucagon-like peptide 1 receptor agonists and free radical scavengers, particularly when levodopa-naïve patients were included. Multifactorial heterogeneity of disease mechanisms, variability of symptoms and their progression are the main causes for these negative results. Additionally an impact of symptomatic dopamine-substituting treatments on the course of Parkinson's disease was demonstrated in clinical studies with monoamine oxidase B inhibitors and dopamine agonists with levodopa therapy as comparator. Neuron transplantation, application of stem cells and their secreted exosomes, or secretomes, are still mainly considered by experimental researchers. Translation into clinical practice is complex or has failed. Stimulation of an existing endogenous repair system in the peripheral and central nervous system is an alternative. Repulsive guidance molecule A (RGMa) inhibits physiologic regeneration in peripheral and central neurons. Blocking of the physiologic effects of this protein initiates endogenous repair in models of acute and chronic neuronal dying as a more general therapeutic concept for chronic neurodegenerative and inflammatory disease.