L-3,4-dihydroxyphenylalanine (L-DOPA) alone or in combination with a peripheral dopa decarboxylase inhibitor (DDI) is the most effective therapeutic agent to improve motor function in most of patients with Parkinson's disease (PPD). However, chronic L-DOPA therapy is associated with of side-effects arising particularly during long-term therapy. Only a small percentage of an exogenous dose of L-DOPA is converted into dopamine (DA) in the brain. The majority is either decarboxylated in peripheral tissues by aromatic amino acid decarboxylase (AAD) to DA, which does not cross the blood-brain barrier, or is O-methylated by catechol-O-methyltransferase (COMT) in both peripheral and brain tissue to yield 3-O-methyldopa (3-OMD). To effectively raise brain DA levels, a large amount of L-DOPA must be administered, often in an oral dose. It has been reported that such large doses of L-DOPA can significantly affect sulphur amino acid metabolite levels. During long-term clinical practice, the decarboxylation of L-DOPA is inhibited, the role of COMT is accentuated and circulating L-DOPA is largely converted into 3-OMD. Therefore, O-methylation of L-DOPA to 3-OMD is linked with conversion of SAM to S-adenosylhomocysteine (SAH). SAH is split into adenosine and Hcy. We evaluated the impact of long-term application of L-DOPA/DDI formulations on plasma methionine (MET), SAM, SAH and tHcy levels in PPD. Patients were from the Institute of Neuropsychiatry, Palermo University. All patients entering the study were examined by neurologists to confirm or exclude the diagnosis of Parkinson’s disease. There were 10 PPD treated with L-DOPA/DDI formulation and 10 healthy controls. Peripheral blood samples were taken in the morning after the subjects had fasted and were off medication for at least 12 hrs. Thus we avoided impact of acute L-DOPA/DDI intake. Plasma tHcy and sulphur metabolite levels were determined by high-performance liquid chromatography (HPLC) as reported. The levels of MET and SAM (approximately 1.21 and 1.32 fold, respectively) in the treated PPD were significantly lower than in the controls while the levels of tHcy (mean 16.6 mmol/L; SD 4.4) were higher compared with controls (mean 9.8 mmol/L; SD 3.4). No significant differences in SAH levels appeared. Based on these findings, we hypothesized that another consequence of high-dose e/or long-term L-DOPA administration might be hyperhomocysteinaemia and may also represent a risk factor for both ischaemic heart and cerebrovascular disease in treated PPD. Besides, the resulting hyperhomocysteinaemia might be increased if L-DOPA therapy is superimposed on a condition known to impair Hcy metabolism, such an enzyme defect or B/acid folic vitamin deficiency.
GUELI MC (2008). Impairment of Methylation cycle in treated patients with Parkinson's disease. In Atti del 53rd National Meeting of the Italian Society of Biochemistry (SIB) and Molecular Biology and National Meeting of Chemistry of Biological Systems Italian Chemical Society (SCI) (pp.13.13-13.13). FIRENZE : Firenze University Press.