Levodopainduced Elevation Of Homocysteine

The occurrence of increased hazard ratios for both ischemic heart and cerebrovascular disease is known in levodopa/DDI-treated parkinsonian patients (33). Long-term levodopa intake supports homocysteine elevation, which has an atherosclerosis-promoting effect. The conversion of levodopa to 3-OMD via the COMT requires Mg2+ as a cofactor and S-adenosylmethionine as a methyl donor (34). Thus O-methylation of levodopa to 3-OMD is associated with the conversion of S-adenosylmethionine to S-adenosylhomocysteine and subsequently homocysteine, which additionally has NMDA agonistic properties (34). Accordingly elevated homocysteine levels appeared in treated PD patients compared to matched controls and significantly correlated to daily levodopa dosage (35-39). Trials on larger cohorts confirmed these previous results (38,40). L-Dopa treated parkinso-nian subjects showed augmented plasma concentrations of homocysteine (41,42). The demonstrated relationship between homocysteine and 3-OMD plasma levels provided further evidence for an impact of levodopa metabolism on homocysteine concentrations. Homocysteine induces substantial impairment of endothelial function and subsequent atherosclerosis (43,44). Atherosclerotic disease of striatal cerebral vessels hypothetically results in subsequent onset of increased susceptibility to impaired mitochondrial energy metabolism, oxidative stress and basal ganglia circuit dysfunction, all of which represent typical, pathophysiologic features of PD (45-48). Moreover exposure of the endothelium to homocysteine induces release of nitric oxide, another excitotoxic compound under suspicion for the contribution of the ensuing neuronal degeneration in PD. Thus long-term application of levodopa/DDI with its consequent impact on homocysteine metabolism may promote vascular disease and hypothetically, the progression of PD, which has already been shown in animal models of neurodegeneration (39,45-49). Other predisposing factors for this homocysteine-mediated toxicity are certain genetic mutations of homocysteine metabolizing and catalyzing enzymes and/or nutrition. From this point of view, monitoring and subsequent therapeutic decrease of homocysteine levels may possibly prevent and/or delay the onset of vascular disease in PD (40,50,51). The relationship between total plasma homocysteine levels and brain atrophy in healthy elderly individuals supports this hypothesis (52). A further confirmatory study result comes from the association found between neurophysiologic dysfunction of peripheral sural nerves and augmented homocysteine levels due to levodopa intake in PD patients (47). This described sensitivity of peripheral sensory nerve may also occur in olfactory nerves, which show clinical signs of dysfunction more in levodopa-treated PD patients than in untreated patients, which were not evaluated for secondary risk factors in terms of homocysteine elevation in detail in these trials. Therefore, one may also assume that olfactory dysfunction as one very early clinical sign of PD is aggravated by levodopa-associated homocysteine elevation, which still needs to be proven (45,53-56). Moreover there are hints that homocysteine elevation appears in neurodegeneration, i.e. Alzheimer's disease or PD patients, independent of any drug intake (57). To conclude, one may state that long-term administration of levodopa is toxic to neuronal function due to the elevation of homocysteine. This may even contribute to the onset of depression, cognitive impairment or even dementia in PD patients in the long run (52,58-60). There are several rather simple ways of treatment for this kind of indirect levodopa toxicity (45,53,61).

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