Levodopa, homocysteine and Parkinson's disease: What's the problem?

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Parkinson patients sometimes complain that their symptoms are not due to their disease, but to their medication. This review shed some light on this problem.

For patients with Parkinson’s disease, dopamine replacement is the treatment of choice, and the most commonly used drug is levodopa (L-dopa), a dopamine precursor. Because dopamine itself cannot cross the blood-brain barrier (BBB) owing to its large molecular weight, L-dopa is administered.

However, L-dopa can easily convert to other structures, such as 3-O-methyldopa catalyzed by the enzyme catechol-O-methyl transferase (COMT) before it crosses the BBB or reaches the brain. To prevent this undesirable conversion, L-dopa is often prescribed along with COMT inhibitors, such as entacapone. Moreover, it can cause serious side effects, such as dyskinesia. It accelerates PD progression by inducing neuronal cell death through self-oxidation.

These treatments of Parkinson's disease tends to further elevate circulating homocysteine levels and peripheral nerves damage. enter image description here High levels of homocysteine in the blood have been associated with certain pathologies, cardiac, neurological, rheumatic or psychiatric. Evidence exists linking elevated homocysteine levels with vascular dementia and Alzheimer's disease.

There is also evidence that elevated homocysteine levels and low levels of vitamin B6 and B12 are risk factors for mild cognitive impairment and dementia. Oxidative stress induced by homocysteine may also play a role in schizophrenia.

Accumulating deficiencies of B12, B6 vitamins and folic acid are presumed to be the substrate for the homocysteine elevation.

So B-vitamin therapy may reduce homocysteine levels. This begs the question of whether Parkinson's disease patients on levodopa should be concurrently treated with ongoing B-vitamin therapy. There is a substantial literature on this topic that has accumulated over the last quarter-century, and this topic is still debated.

This review summarizes the relevant literature with the aim of approximating closure on this issue. Also, noteworthy is that Parkinson's disease patients with renal insufficiency may not tolerate cyanocobalamin, the standard oral B12 supplement due to facilitation of renal decline.

Here are some key points: • Levodopa treatment of Parkinson's disease (PD) elevates circulating homocysteine levels. • Elevated homocysteine and/or B-vitamin depletion correlates with an increased risk of cognitive decline. • Lifetime monitoring of B-vitamin levels could address this problem. • It may be necessary to prescribe oral B12, B6, folic acid to levodopa-treated PD patients. • Levodopa-treated PD patients with renal insufficiency should take methylcobalamin rather than cyanocobalamin.

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