[imark3000]

Toxic effects of L-DOPA on mesencephalic cell cultures: protection with antioxidants
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B. Pardoa, M.A. Mena, a, M.J. Casarejosa, C.L. Paínoa and J.G. De Yébenesb

aDepartamento de Investigación, Hospital Ramón y Cajal, Madrid ,Spain

bServicio de Neurología, Fundación Jiménez Díaz, Madrid ,Spain

Accepted 28 February 1995. Available online 6 April 2000.

Abstract
The toxicity of L-3,4-dihydroxyphenylalanine (L-DOPA) was studied in neuronal cultures from rat mesencephalon. The survival and function of DA neurons were assessed by the number of tyrosine hydroxylase-positive (TH+) cells and3H-DA uptake and those non-DA neurons by the exclusion of Trypan blue and the high-affinity3H-GABA uptake. L-DOPA was toxic for both DA and non-DA neurons. DA neurons were more severely affected than non-DA neurons after short periods of treatment and with exposure to a low dose of L-DOPA (25 vs. 100 μM) and less selectively affected after 1 or 2 days of treatment. After incubation with L-DOPA, a disruption of the neuritic network and an overall deterioration were observed, more evident for TH+ cells in the whole culture. Auto-oxidation to quinones is responsible in part for L-DOPA toxicity in non-DA neurons since the levels of quinones correlated well with the severity of cell death in the cultures. The damage of DA neurons took place before the rising of quinones, suggesting that quinones are not essential in L-DOPA toxicity for DA neurons. Antioxidants, such as ascorbic acid and sodium metabisulfite, completely prevented L-DOPA-induced quinone formation as well as the death of non-DA neurons. In contrast, they could only partially prevent the damage produced by L-DOPA in DA neurons. Mazindol, a selective inhibitor of DA uptake, protected TH+ cells from L-DOPA.

[imark3000]

[edit] Side effectsThe side effects of L-DOPA may include:

Hypotension, especially if the dosage is too high
Arrhythmias, although these are uncommon
Nausea, which is often reduced by taking the drug with food, although protein interferes with drug absorption
Gastrointestinal bleeding
Disturbed respiration, which is not always harmful, and can actually benefit patients with upper airway obstruction
Hair loss
Disorientation and confusion
Extreme emotional states, particularly anxiety, but also excessive libido
Vivid dreams and/or insomnia
Auditory and/or visual hallucinations
Effects on learning; there is some evidence that it improves working memory, while impairing other complex functions
Somnolence and narcolepsy
A condition similar to stimulant psychosis
Although there are many adverse effects associated with L-DOPA, in particular psychiatric ones, it has fewer than other antiparkinsonian agents, such as anticholinergics and dopamine receptor agonists.

More serious are the effects of chronic levodopa administration, which include:

End-of-dose deterioration of function
On/off oscillations
Freezing during movement
Dose failure (drug resistance)
Dyskinesia at peak dosePossible serotonin depletion: Recent studies have demonstrated that use of L-DOPA without simultaneously giving proper levels of serotonin precursors depletes serotonin
Possible dopamine dysregulation: The long-term use of L-DOPA in PD has been linked to the so-called dopamine dysregulation syndrome.[3]
Clinicians will try to avoid these side effects by limiting L-DOPA doses as much as possible until absolutely necessary.

[edit] ToxicitySome scientific studies suggest a cytotoxic role in the promotion and occurrence of adverse effects associated with L-DOPA treatment.[4] Though the drug is generally safe in humans, some researchers have reported an increase in cytotoxicity markers in rat pheochromocytoma PC12 cell lines treated with L-DOPA.[5] Other authors have attributed the observed toxic effects of L-DOPA in neural dopamine cell lines to enhanced formation of quinones through increased auto-oxidation and subsequent cell death in mesencephalic cell cultures.[6][7] Though L-DOPA is generally considered safe, some controversy surrounds its use in the treatment of PD, given some data indicating a deleterious effect on intracellular and neuronal tissue involved in the pathogenesis of the disease.[8]

[lindylanka]

Imad,
Around 7 of the side-effects that you listed for l-dopa are also symptoms of b12 deficiency. There are some studies that say that l-dopa treated patients are low in b12 and folate. It might be worth chasing this up if anyone is getting more than a few on the list....

Lindy