ABSTRACT
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss brain stem neurons and dysregulation of downstream basal ganglia motor pathways. Understanding the pathophysiology has led to the development of treatments that improve the symptoms of PD. Early pathological studies identified the loss of pigmented neurons in the substantia nigra of the parkinsonian brain.1 The degenerated nigrostriatal tract produced the neurotransmitter dopamine. As dopamine does not cross the bloodbrain barrier, L-dihydroxy-phenylalanine (LD) the metabolic precursor of dopamine was utilized to replenish the loss of dopamine. Though it was profoundly effective in alleviating symptoms of PD, LD was not considered an ideal therapy for PD.2 LD had a short half-life. Conversion of LD was dependent on the presence of dopa decarboxylase, an enzyme that diminished in concentration in the degenerating nigrostriatal tract.3 In addition, the supraphysiologic levels of dopamine nonspecifically stimulated dopamine receptors, resulting in severe limbic, sympathetic, and gastrointestinal adverse effects. Finally, in vitro studies suggested that LD promoted apoptosis and oxidative metabolites in nigrostriatal neurons.4,5
The natural history of Parkinson’s disease changed after the advent of LD. Morbidity and mortality was posi-tively impacted with widespread use of L-dopa, despite continued in vitro evidence of neuronal damage.6 As degeneration of numerous nondopaminergic nuclei had also been reported, in retrospect, it is remarkable that replacement therapy works so well in compensating for impulse-driven release of endogenous dopamine. In no other syndrome or disease has simple exogenous replenishment of a neurotransmitter provided a therapeutic response. The pharmacologic treatment of PD remains dominated by strategies designed to compensate for the loss of dopaminergic neurons in the substantia nigra. Clinical studies continue to confirm the efficacy of LD as well as dopamine agonists in improving the symptoms of Parkinson’s disease. Agonist therapy has not improved upon the potency of response obtained with L-dopa after the addition of the adjunctive medications designed to decrease the peripheral decarboxylation.
