Efficacy of L-DOPA therapy in Parkinson's disease

L-3,4-dihydroxyphenylalanine (L-DOPA) isa classical example of an amino acid that isan immediate precursor to dopamine andhas been developed as an effective therapeuticagent for a neurodegenerative disease.Dopamine deficiency is known to be acore pathogenic event in Parkinson's disease(PD). It is the main neurotransmitter responsiblefor modulation of motor behaviour.Peripherally given, L-DOPA is transportedinto the brain and upon decarboxylationconverted into dopamine. L-DOPA pharmacotherapyis used as a symptomatic treatmentof PD as it restores dopamineneurotransmission. Since L-DOPA can alsobe decarboxylated in the periphery, andperipherally formed dopamine is not able tocross the blood-brain barrier, inhibition ofthe peripheral decarboxylation increasesbioavailability of L-DOPA in the brain. Aninitial satisfactory clinical response toL-DOPA is invariably hampered later in thecourse of the disease, mainly due to progressionof the neurodegenerative changes inthe brain. In addition, side effects suchas motor fluctuations and abnormal involuntarymovements become a significantproblem for patients with advanced disease.Moreover, it is thought that pulsatile administrationof L-DOPA is one of the mostimportant underlying trigger factors forinduction and maintenance of these motorcomplications. This mode of stimulation isthought to lead to abnormal changes inbasal ganglia neurons at the molecularlevel. These plastic changes can be reducedor avoided if dopaminergic replacementis done in a more continuous andphysiologic manner. Currently, continuousdopaminergic stimulation can be achievedby using long-lasting drug formulations orcontinuous L-DOPA infusion pumps. Inaddition to these peripheral administrationapproaches, recently, viral-mediated intrastriatal3,4-dihyroxyphenylalanine (DOPA)delivery strategies have been developed asan alternative treatment in Parkinson'sdisease.