Abstract
BackgroundA combination of levodopa (L-DOPA) and carbidopa is the most commonly-used treatment for symptom management in Parkinson's disease. Studies have shown that concomitant use of a COMT inhibitor is highly beneficial in controlling the wearing-off phenomenon by improving L-DOPA bioavailability as well as brain entry. The present study sought to determine whether (-)-epigallocatechin-3-gallate (EGCG), a common tea polyphenol, can serve as a naturally-occurring COMT inhibitor that also possesses neuroprotective actions.Methodology/Principal FindingsUsing both in vitro and in vivo models, we investigated the modulating effects of EGCG on L-DOPA methylation as well as on chemically induced oxidative neuronal damage and degeneration. EGCG strongly inhibited human liver COMT-mediated O-methylation of L-DOPA in a concentration-dependent manner in vitro, with an average IC 50 of 0.36 µM. Oral administration of EGCG moderately lowered the accumulation of 3-O-methyldopa in the plasma and striatum of rats treated with L-DOPA + carbidopa. In addition, EGCG also reduced glutamate-induced oxidative cytotoxicity in cultured HT22 mouse hippocampal neuronal cells through inactivation of the nuclear factor κB-signaling pathway. Under in vivo conditions, administration of EGCG exerted a strong protective effect against kainic acid-induced oxidative neuronal death in the hippocampus of rats.Conclusions/SignificanceThese observations suggest that oral administration of EGCG may have significant beneficial effects in Parkinson's patients treated with L-DOPA and carbidopa by exerting a modest inhibition of L-DOPA methylation plus a strong neuroprotection against oxidative damage and degeneration.
Highlights
Parkinson’s disease (PD) is a chronic and progressive neurological disorder characterized by uncontrolled muscle tremor, rigidity, and bradykinesia
We sought to investigate the beneficial effects of EGCG, a well-known tea polyphenol, on L-DOPA Omethylation and oxidative neurodegeneration in an effort to explore the intriguing possibility that certain dietary polyphenols may serve as effective COMT inhibitors as well as neuroprotective agents
We found that EGCG, a quantitatively-abundant polyphenol contained in tea beverages, can strongly inhibit LDOPA methylation in vitro catalyzed by human liver cytosolic COMT (Figure 3A), with a high inhibition potency (IC50 of 0.1– 0.6 mM)
Summary
Parkinson’s disease (PD) is a chronic and progressive neurological disorder characterized by uncontrolled muscle tremor, rigidity, and bradykinesia. Studies have shown that the use of a COMT inhibitor is helpful in controlling the wearing-off phenomenon in PD patients by prolonging the circulating half-life of L-DOPA and improving its brain entry [4]. When this multi-drug combination strategy is used, the effective dose of L-DOPA is reduced, and so are some of the untoward effects that are likely exerted by L-DOPA metabolites, such as dopamine and 3-OMD [5]. Studies have shown that concomitant use of a COMT inhibitor is highly beneficial in controlling the wearing-off phenomenon by improving L-DOPA bioavailability as well as brain entry. The present study sought to determine whether (-)-epigallocatechin-3-gallate (EGCG), a common tea polyphenol, can serve as a naturallyoccurring COMT inhibitor that possesses neuroprotective actions
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