Recent studies have suggested that free radicals play a key role in the progression of Parkinson’s disease (PD). Although levodopa is the most effective therapeutic agent in the treatment of PD and has improved the quality of life and increased life expectancy, its beneficial effects are not permanent. Long-term treatment with levodopa produces a variety of side effects in patients with PD. We have previously reported that levodopa may accelerate the progression of PD in certain patients. To determine whether neuronal damage can be caused by levodopa overdoses, we estimated the effects of levodopa on free radical formation. Electron spin resonance spectrometry showed that levodopa oxidation produced levodopa radicals. Furthermore, chronic administration of levodopa increased thiobarbituric acid-reacting substances (TBARS) in various brain regions of 6-hydroxydopamine (6-OHDA; i.c.v.)-pretreated mice, although levodopa administration in control mice had no effect on TBARS. These results indicate that high dose levodopa accelerates neuronal degeneration in some parkinsonian brains. We then evaluated the protective effects of bromocriptine on striatal dopaminergic neurons, with determination of dopamine (DA) and its metabolites as markers. Pretreatment of bromocriptine completely protected mice against the decreases in striatal DA and its metabolites induced by intracerebroventricular injection of 6-OHDA, while levodo-pa/carbidopa had no protective effects. Furthermore, in an in vitro system that generated "OH from FeSO4-H2SO4, bromocriptine dose-dependently scavenged ‘OH. These findings clearly indicate that bromocriptine has neuroprotective effects against neurotoxins such as 6-OHDA, probably due in part to its free radical scavenging activity. They further indicate that the early introduction of bromocriptine to PD therapy is superior to treatment with levodopa alone. Combination therapy with a DA agonist such as bromocriptine and low doses of levodopa are likely to create a better balance between D2 and Dl receptors, and to maintain normal DA neurotransmission for longer peri