EGCG: Significant Advance in Treatment of Parkinson’s Disease
The most common treatment for Parkinson’s disease (PD) is a combination of levodopa (L-Dopa) and carbidopa. The L-Dopa serves as the precursor for production of dopamine in the brain where its deficiency (in the striatum) can result in severe movement disorders typical of PD. The carbidopa is a dopa decarboxylase inhibitor and is combined with the L-Dopa because it restricts the peripheral conversion of L-Dopa to dopamine, allowing the L-Dopa to enter the brain and be converted there where it is needed, while reducing the peripheral effects of increased dopamine, such as lowered blood pressure.
A new paper1 now reports that taking EGCG along with L-Dopa and carbidopa results in a significantly increased beneficial effect of therapy by modestly inhibiting the methylation of L-Dopa by the enzyme catecholamine-O-methyltransferase (COMT), thus preventing the rapid conversion of L-Dopa by the liver to inactive 3-O-methyldopa. “Studies have shown that the use of a COMT inhibitor is particularly helpful in controlling the wearing-off phenomenon in PD [Parkinson’s disease] patients by prolonging the half-life of L-Dopa and improving its brain entry.”1
The researchers got the idea for testing the effectiveness of EGCG as a COMT inhibitor as part of Parkinson’s disease therapy from the fact that catechol-containing bioflavonoids and tea catechins have been identified as good substrates for COMT. In addition, these compounds have also been found to be strong inhibitors of liver COMT-mediated O-methylation of endogenous catechol estrogens. “Among these dietary compounds, EGCG was found to be the most potent inhibitor, with an IC50 [concentration required to inhibit the enzyme by 50%] of approximately 0.1 μM when 2-hydroxyestradiol was used as substrate.” The authors of the paper1 also note that “[t]he findings of this study may also shed a mechanistic light on the recent epidemiological observation suggesting that regular tea drinking is associated with a reduced risk of PD.”
Male Sprague-Dawley rats were the experimental animal in the study. The researchers note that an earlier study reported that EGCG given at a daily oral dose of 500 mg/kg for 13 weeks was not toxic in rats. The doses used on the rats in this study1 were 100 and 400 mg/kg, given two hours before L-Dopa/carbidopa. Results showed that the rats treated with 400 mg/kg had levels of 3-OMD in circulation and in the striatum that were reduced by approximately 30%, revealing the decrease in L-Dopa methylation.
The authors report that earlier human studies showed that “circulating concentrations after oral administration of 800 mg EGCG are higher than its effective IC50 concentrations required for inhibiting L-Dopa methylation in vitro. Therefore, it is possible that oral administration of EGCG may readily reach therapeutically-effective concentrations needed for inhibiting L-Dopa methylation in PD patients.”1 Moreover, the authors suggest, although daily intake of EGCG through tea drinking may not yield the therapeutically effective concentration, there are other polyphenolic components contained in tea and coffee that also contain the same catecholic structures as does L-Dopa, thereby making them good substrates of and thus inhibitors of COMT.
Interestingly, the authors1 suggest that the reduction in striatal 3-OMD level may aid in reducing side effects associated with L-Dopa/carbidopa therapy in PD. One study cited by the authors found that the plasma levels of 3-OMD in patients with dyskinesia were significantly higher than those in patients without dyskinesia. Also, they note that it has been suggested that 3-OMD accumulation following long-term L-Dopa treatment might contribute to progression of the neurodegeneration in PD patients.
- Ki Sung Kang et al. Dual beneficial effects of (-)-epigallocatechin-3-gallate on levodopa methylation and hippocampal neurodegeneration: in vitro and in vivo studies. PLoS One. 5(8):e11951 (Aug. 2010).