Possible Interaction: Levodopa and S-Adenosylmethionine

“Because SAM in higher dosages may also counteract the antiparkinsonian efficacy of levodopa according to animal trials, this SAM increase may hypothetically contribute to the onset of wearing-off phenomena and other clinical signs of limited efficacy of levodopa during long-term treatment with levodopa in PD patients.”

“The SAM increase after levodopa intake may exert both a certain antidepressant and cognitive function improving effect.”

“Therefore, SAM could contribute to a decreased efficacy of levodopa in the long term.”

“In the folate-deficient mouse model, l-dopa resulted in a marked depletion of SAM and an increase in SAH in various brain regions with parallel downregulation of PP2A methylation and increased Tau phosphorylation.”

“There is a particular interest in investigating these effects in Parkinson disease where Levodopa treatment is known to increase the consumption of S-adenosylmethionine.”

“Background: Studies have demonstrated that S-adenosylmethionine could effectively affect the clinical wearing-off phenomena of levodopa , an antiparkinsonian agent; however, the detailed mechanisms for this effect need to be further clarified.”

“Conclusions: These observations suggested that methyl donor S-adenosylmethionine could act as a potential agent against vascular endothelial growth factor-A-related diseases induced by levodopa treatment.”

“Meanwhile, S-adenosylmethionine could significantly abolish the increased angiogenesis and cell viability induced by levodopa.”

“Here we show that l-Dopa administration in hyperhomocysteinemic PD patients is able to lower intracellular concentration of S-Adenosylmethionine (AdoMet) in erythrocytes (RBC), while the occurrence of hyperhomocysteinaemia causes a significant increase in S-Adenosylhomocysteine (AdoHcy) level.”

“Raising levodopa concentrations in the central nervous system caused a fall in CSF S-adenosyl-methionine concentration and a rise in CSF 3-methoxytyrosine concentration.”

“To determine whether levodopa reduces the levels of S-adenosylmethionine in the human central nervous system, cerebrospinal fluid (CSF) concentrations of S-adenosylmethionine, methionine, 3-methoxytyrosine, levodopa and 5-methyltetrahydrofolate were measured in six children with dopamine deficiency before and after treatment.”

“Furthermore, many of the biochemical changes seen in PD resemble changes that could occur if SAM-dependent methylation reactions are increased in the brain, and interestingly l-DOPA , the most effective drug used to treat PD, reacts avidly with SAM.”

“ L-dopa , the major treatment for Parkinson's disease (PD), depletes S-adenosyl-L-methionine (SAM).”

“ SAM may physiologically antagonize the effects of L-dopa and biochemically decrease the concentrations of L-dopa and dopamine.”

“Methionine, dimethionine and SAM all protected DA neurons against damaged induced by L-dopa.”

“But 2, 3 and 4 consecutive injections of L-dopa , given at 45 min intervals, depleted SAM by 60, 64 and 76% and increased SAM/SAH to 818, 896, and 1524%.”

“ L-dopa (50, 100 …-dependently depleted SAM from 24.9 +/- 1.7 nmol/g to 13.0 +/- 0.8, 14.7 +/- 0.8 and 7.7 +/- 0.7 … from 1.88 +/- 0.14 to 3.43 +/- 0.26, 4.22 +/- 0.32 and 6.21 +/- 0.40 nmol/g.”

“The data show that L-dopa depletes SAM , and increases methylation 4-5 times more than dopamine, therefore, methylation may play a role in the actions of L-dopa.”

“The results show that, at 0.5 hr, L-dopa (100 mg/kg) decreased the methyl donor, S-adenosylmethionine (SAM) by 36%, increased its metabolite S-adenosylhomocysteine (SAH) by 89% and increased methylation (SAH/SAM) by about 200%.”