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We read with interest the recent excellent review by Reynolds on the role of folic acid and the risks and benefits of its supplementation in the nervous system.1 It emphasises the beneficial importance of folate on the numerous methylation processes in combination with S-adenosylmethionine (SAM), which donates its methyl group to prevent hyperhomocysteinaemia.1 However SAM deficiency, which is associated with, for example, cognitive decline and/or mood disturbances, and increased total homocysteine levels, which support onset of vascular disease, may also caused by drugs, for example, levodopa.2,3 Levodopa is administered with dopa decarboxylase inhibitors (DDI) to prevent its peripheral degradation. This increases conversion of levodopa to 3-O-methyldopa (3-OMD) by the ubiquitious enzyme catechol-O-methyltransferase (COMT) in blood, peripheral tissues and in nigrostriatal neurons.2,3 COMT requires Mg2+ as cofactor and SAM as methyl donor. Thus O-methylation of levodopa to 3-OMD is associated with conversion of SAM to S-adenosylhomocysteine and subsequently homocysteine.2,3 We already demonstrated this association between homocysteine, SAM and 3-OMD in treated Parkinson’s disease (PD) patients,2,3 who often suffer from depression and bradyphrenia in the course of the disease and show an increased mortality risk of vascular disease.4 The objective of our follow up study2,3 was to determine total plasma homocysteine in 212 levodopa treated and 29 previously untreated PD patients and 110 controls. Standardised measurement of total homocysteine plasma concentrations with high performance liquid chromatography was only performed in subjects with no metabolic disturbances, like diabetes mellitus, hypertension, reduced levels of vitamin B6, cobalamine and/or folic acid or neurological diseases other than PD. Each PD patient fasted and was withdrawn from drug treatment for at least 12 hours before taking of blood samples in the morning. All participants gave informed consent, the local ethical committee approved this study. Homocysteine levels were significantly (analysis of covariance F(dF 2, dF 346) =17.5, p=5.9E-08; post hoc analysis (Tukey’s HSD test): levodopa treated PD patients compared with controls: p=2.2E-05, previously untreated compared with levodopa treated PD patients: p=0.005; previously untreated PD patients compared with controls: p=0.92) increased in levodopa/DDI treated PD patients (17.3 (8.2) μmol/l (mean (SD)) compared with previously untreated PD patients (11.4 (5.8) μmol/l) and controls (12.2 (5.5) μmol/l). There was no significant impact of covariates age, sex, daily levodopa dose, and Hoehn and Yahr Stage (data not shown). An effective therapeutic approach for reduction of homocysteine levels is additional folic acid supplementation, as folic acid and cobalamine catalyse and increase metabolism of homocysteine to methionine,2,3 or, hypothetically, application of peripherally acting COMT inhibitors as adjunct to levodopa/DDI treatment.3 Methionine acts in combination with pyridoxalphosphate or S-methyl-α-keto-butyric acid as a strong scavenger of strong oxidants, which in turn induce endothelial dysfunction.5 Homocysteine induced endothelial dysfunction may further promote atherosclerotic disease in striatal cerebral vessels with subsequent onset of differential susceptibility to impaired energy metabolism, oxidative stress, and basal ganglia dysfunction.5 Endothelial response to homocysteine depends on the synthesis of nitric oxide.5 Exposure of the endothelium to homocysteine induces release of nitric oxide, a further excitotoxic compound under suspicion for the contribution of the ensuing neuronal degeneration in PD.2,3,5 Nitric oxide and reduced methionine levels support increased appearance of free radicals, in particular superoxide. Superoxide and nitric oxid generate peroxynitrite.2,3,5 Peroxynitrite mediates tyrosine nitration, which further impairs activity of a variety of enzymes and inactivates tyrosine kinases.2,3,5 These kinases are used by a variety of neuroprotective and neurorestorative growth factors, for instance glial cell line derived neurotrophic factor.2,3 Accordingly in vitro trials showed neurotoxic effects of homocysteine and its oxidation product homocysteic acid on various types of cultured human neuronal cell lines and their excitotoxic activity partially via N-methyl-D-aspartate agonistic and mimicking properties.5 In conclusion, additional folic acid supplementation with concomitant lowering of total homocysteine levels in levodopa/DDI treated PD patients will hypothetically reduce progress of PD and increased hazard ratios for both ischaemic heart—and cerebrovascular disease in treated PD patients.4
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