Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson's disease patients

Abstract

Homocysteine (Hcy) is a risk factor for vascular diseases, cognitive impairment, and dementia. Elevated plasma concentrations of Hcy have been found recently in Parkinson's disease (PD) patients treated with levodopa, suggesting that levodopa is a cause of hyperhomocysteinemia (HHcy). The mechanism underlying HHcy in PD is the O-methylation of levodopa catalyzed by catechol-O-methyltransferase (COMT) that produces S-adenosylhomocysteine, which is hydrolyzed rapidly to Hcy. COMT inhibitors (COMT-I) are used currently in the treatment of PD; however, no study has assessed the effects of COMT-I administration on Hcy concentrations in PD patients. We compared plasma levels of Hcy, B12, and folate in 26 PD patients treated with levodopa, 20 PD patients treated with levodopa + COMT-I, and 32 controls. No significant differences were found in vitamin B12 levels, whereas folate concentrations were significantly lower in the levodopa-treated group. Plasma Hcy was increased significantly in the two groups of PD patients and was significantly lower in the group treated with levodopa + COMT-I. Statistical analysis showed that the difference in mean Hcy levels observed among PD patients was related to the addition of COMT-I, rather than to folate concentrations. We conclude that levodopa treatment increases plasma Hcy and the addition of COMT-I effectively reduces HHcy.

Evaluation of the Current Evidence on Hyperhomocysteinemia in Neurological Diseases

“…41 The effect of combining COMT inhibitors with L-dopa to avoid HHcy is inconclusive. [42][43][44] The available evidence suggests that folate, vitamin B 6 , and vitamin B 12 , but not COMT inhibitors, are the most important modifiers of the effect of L-dopa on Hcy levels. [45][46][47] It seems that higher concentrations of Hcy in PD patients are generally associated with poor progression of the disease.…”

Is There the Preventive Effect of COMT-inhibitor on Parkinson's Disease Associated with Dementia?

“…This is due to the O-methylation of levodopa, which is catalyzed by the enzyme catechol-O-methyltransferase (CO-MT) and requires S-adenosylmethionine (SAM) as the methyl donor for the production of S-adenosylhomocysteine (SAH), which is rapidly hydrolyzed to hcy. This chronic increase in hcy synthesis exceeds the capacity of cells to metabolize hcy, leading to elevated serum hcy levels [8]. Serum hcy levels in patients with PD treated with levodopa are specifically thought to be elevated due to increased synthesis from the metabolism of levodopa by COMT [1,4,8].…”

“…This chronic increase in hcy synthesis exceeds the capacity of cells to metabolize hcy, leading to elevated serum hcy levels [8]. Serum hcy levels in patients with PD treated with levodopa are specifically thought to be elevated due to increased synthesis from the metabolism of levodopa by COMT [1,4,8]. A previous animal study demonstrated that pre-treatment with a COMT inhibitor can block the elevation of serum hcy levels when levodopa is given [9].…”

Levodopa en la enfermedad de Parkinson: ¿Qué hemos aprendido?

“…El uso de inhibidor de la DDC en conjunto con levodopa genera que la vía metabólica se desvíe preferentemente por la COMT, aumentando los niveles de homocisteína 42 . Ellos se elevan sobre los valores normales en portadores de EP tratados con [41][42][43] . Estudios en otras poblaciones de pacientes han demostrado que la homocisteína es un factor de riesgo para eventos vasculares y aparición de deterioro cognitivo 44 .…”

“…El uso de vitaminas B12, B6 y ácido fólico reducen los niveles de homocisteína, lo mismo ocurre al emplear inhibidores de la COMT 43,45 . Aún falta información para hacer recomendaciones sobre este aspecto 46 .…”