Levodopa radical

Levodopa has the potential to become a levodopa radical (Ogawa etal. 1993) ... 

Attention has been given to the possibility that some of the above motor effects may arise from a metabolite of levodopa. The prime suspect is OMD which has a half-life of some 20 hours and reaches plasma concentrations three- to fourfold those of dopa. Suggestions that it may compete with dopa for entry across the blood-brain barrier or act as a partial agonist (effective antagonist) have not been substantiated experimentally although it does reduce DA release from rat striatal slices. Also if free radical production through deamination of DA is neurotoxic (see below) then this would be increased by levodopa. 

Figure 15.11 Possible scheme for the formation of free radicals from the metabolism of dopamine. Normally hydrogen peroxide formed from the deamination of DA is detoxified to H2O along with the production of oxidised glutathione (GSSG) from its reduced form (GSH), by glutathione peroxidase. This reaction is restricted in the brain, however, because of low levels of the peroxidase. By contrast the formation of the reactive OH-radical (toxification) is enhanced in the substantia nigra because of its high levels of active iron and the low concentration of transferin to bind it. This potential toxic process could be enhanced by extra DA formed from levodopa in the therapy of PD (see Olanow 1993 and Olanow et al. 1998)...

Ogawa, N., Edsmatsu, R, Mizukawa, K., Asanuma, M., Kohno, M. and Mori, A. (1993). Degeneration of dopaminergic neurons and free radicals, possible participation of levodopa. Adv. Neurol. 60, 242-251. 

This patient had taken ecstasy 10 times during the year before, the last time about 3 months before the onset of symptoms. Apart from marijuana, he denied using other substances. He was treated with maximal tolerable doses of levodopa and pramipexole, without improvement. The authors reported that they had no explanation for this patient s symptoms, other than the use of ecstasy. They felt that the parkinsonian symptoms most closely resembled MPTP-induced parkinsonism. They further postulated that this could be a delayed neurotoxic effect of ecstasy in the substantia nigra and striatum and could have occurred as a result of neuronal damage by free radicals. 

Parkinson s disease is caused by the oxidative stress-induced loss of dopaminergic neurons and can be effectively treated with levo-dopa in combination with dopa decarboxylase inhibitors such as carbidopa or catechoi-0-methyltransferase inhibitors such as tolca-pone. Levodopa is well known to increase the life spans of patients with Parkinson s disease. It may do this by enhancing brain dopamine levels and inhibiting tyrosine hydroxylase, which produces oxygen radicals. Several dopamine receptor agonists are available for use in Parkinson s disease and are extensively used in patients suffering from the adverse effects of levodopa. Anticholinergics such as trihexyphenidyl are also used in Parkinson s disease. 

Due to the on/off phenomena and concerns about the exact role of dopamine s contribution to free radical generation and tissue damage, most practitioners use levodopa only when the symptoms of PD cause functional impairment. When levodopa levels are maintained constant by intravenous infusion, dyskinesias and fluctuations are greatly reduced, and the clinical improvement is maintained for up to several days after returning to oral levodopa dosing. A sustained-release formulation and division of the total daily dose into more frequently administered portions have been used to overcome the on/off phenomenon. 

Ever since the introduction of levodopa there have been concerns that it may be neurotoxic, particularly towards neurons in the substantia nigra, which are in any case depleted in Parkinson s disease. There is a plausible mechanism for this, through generation of free radicals. The evidence from cell culture studies, animal studies, and clinical data has been reviewed, and the authors concluded that the culture experiments are confounded by lack of ascorbate in the medium, which would act as an important protective agent, as it appears to do in vivo in animals, notably in primates [95 ]. The clinical data have failed to support the idea that levodopa accelerates striatal neuronal loss. However, the evidence is contradictory, and it seems unlikely that even after 50 years we shall get a definitive answer. 

A number of other quinone drugs possess antitumor activity, for example, p-lapachone and those derived from levodopa and dopamine . An oxy radical mechanism for the anticancer action was invoked . 

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