Free-radical toxicity and antioxidant medications in Parkinson's disease

Parkinson's disease is a movement disorder characterized by the progressive degeneration of neurons located in the substantia nigra.(1,2) These neurons synthesize and secrete dopamine, and the loss of dopaminergic influence on other structures in the basal ganglia leads to the classic parkinsonian symptoms of resting tremor, bradyb kinesia, rigidity, and postural instability.(1,3) Pharmacologic treatment of Parkinson's disease traditionally has centered on administering medications that restore dopaminergic influence in the basal ganglia. The cornerstone of treatment usually consists of levodopa (L-dopa), which is the immediate precursor to dopamine.(1,2) Levodopa crosses the blood-brain barrier, where it is then converted to dopamine, thus helping reestablish dopaminergic effects. The administration of L-dopa can often produce dramatic improvements in parkinsonian symptoms, especially during the early stages of the disease.(1) The effects of L-dopa, however, often diminish after only a few years of continuous use, and this drug often is ineffective in the advanced stages of Parkinson's disease.(1,2) More importantly, the administration of L-dopa does not seem to delay the progression of Parkinson's disease.(2,3) That is, merely increasing dopaminergic influence in the basal ganglia does not prevent the deterioration of neurons in the substantia nigra. Recent efforts, therefore, have focused on identifying the factors responsible for neuronal degeneration and on developing medications that might be able to delay nigral cell death. The exact cause of Parkinson's disease still is not known, but there is a growing body of evidence that nigral neurons may be damaged by cytotoxic substances known as free radicals.(4-9) Free radicals are thought to be produced locally within the basal ganglia and to lead to progressive damage to and death of substantia nigra neurons in susceptible individuals.(6,7,9) The purpose of this update is to present evidence that free-radical toxicity may be the underlying cause of nigral cell deterioration in persons with Parkinson's disease. Possible pharmacologic strategies for dealing with this free-radical-induced damage also are addressed.