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have been proposed to explain the development of LID. LID may emerge as a consequence of abnormal flctuations in synaptic DA levels induced by L-DOPA treatment5. Glutamate receptors hyperactivity was also suspected to induce LID6–9. There is evidence of cross talk between glutamate receptors and L-DOPA via homocysteine (Hcy)10. In clinical practice, L-DOPA is combined with DOPA decarboxylase inhibitors (DDI)11. This increases the plasma half-life of L-DOPA and the clinical effects of L-DOPA on motor behaviour of PD patients are improved. DDI action diverts L-DOPA metabolism towards catechol-Omethyltransferase enzyme (COMT)11. Consequently, an increased synthesis of the L-DOPA metabolite 3-O-methyldopa (3-OMD) occurs11. 3-OMD accumulates in particular during repeated L-DOPA/DDI application11. Moreover, the COMT enzymatic activity requires S-adenosylmethionine (SAM) as the methyl donor10. Therefore O-methylation of L-DOPA to 3-OMD is associated with the conversion of SAM to S-adenosylhomocysteine (SAH), which can subsequently be transformed to Hcy10. Hcy is an endogenous glutamate receptor agonist12–15 acting on N-methyl-Daspartate (NMDA) receptors12,16. In response to excitatory stimulations the brain cells produce homocysteic acid from Hcy17. Homocysteic acid is an oxidative product that functions as an excitatory neurotransmitter by activating NMDA receptors18. Folate functions as a cofactor for enzymes involved in amino acid metabolism and nucleic acid synthesis10. Abstract Introduction Levodopa treatment in Parkinson’s disease can lead to elevated homocysteine levels. Increased homocysteine levels may accelerate dopaminergic cell death in Parkinson’s disease through neurotoxic effects. Homocysteine has been found to induce neurological dysfunction via excitotoxic stress. Accordingly, homocysteine-induced toxicity is mediated by glutamate receptors. The neurological pathologies associated with hyperhomocysteinaemia are hypothesised to be caused by oxidative stress, excitotoxicity via glutamate receptors, and DNA hypomethylation. Low vitamin B status combined with polymorphisms in pathway-specific gene mutations can lead to hyperhomocysteinaemia. Consequently, lowering homocysteine level in the blood by B-complex vitamin may relieve Parkinson’s disease and motor complication associated with levodopa therapy. Alternatively, medicinal plants-derived antioxidants have been demonstrated to reduce lipid peroxidation and enhance activities and levels of endogenous antioxidants. Therefore, medicinal plants might be considered as important remedies to improve the pathological alterations associated with the oxidative stress-related diseases such as Parkinson’s disease and levodopa-induced dyskinesias. This review surveys the molecular mechanisms of levodopa-induced dyskinesias, and sheds the light into the potentials of dietary supplementations and traditional medicine as therapeutics in synergy with levodopa therapy. Conclusion Novel approaches to improve the bioavailability of medicinal plants might be their use as an adjunctive therapy with levodopa or glutamate receptors antagonists or vitamin B supplementation. Pre-clinical and clinical investigations of this treatments regime need to be undertaken.

oa biotechnology

Homocysteine and glutamate receptors in the neuronal dysfunction and cell death in levodopa therapy: Are B-complex vitamins and herbal medicine the panacea?