USP that might not be the best idea. L-dopa is REALLY questionable and hotly debated topic for neurotoxicity.
i need to look into this further before buying powerfull next time.
You are a stating an opinion and not claiming much. We dove head first into all the research. He is an exert. 1-c is closely related to L-dopa but increases dopamine to a great extent.
A 1986 case report found that a 76 year old man who was treated with Sinemet ® L-dopa over 4 years, equivalent to 8-10kg of plain L-dopa. (19). The authors concluded: “Nevertheless, this case report emphasises that the burden of proof for a cytotoxic effect of levodopa in man remains with its proponents.” (19).
L-Dopa to the rescue
Many studies have actually found L-dopa to have a “neurotrophic”, or health-promoting effect on DA neurons. Thus Murer and colleagues report: “Our results clearly indicate the absence of toxicity of a pharmacologically effective chronic levodopa treatment on remaining dopaminergic neurons of rats with moderate and severe 6-OHDA-induced lesions. In addition, they clearly suggest that chronic levodopa administration induced a partial recovery of remaining dopaminergic neurons in moderately lesioned rats.” (14). Mena et al cultured DA neurons with cortical astrocytes (glial cells), then fed them L-dopa. “This study demonstrates that L-dopa has neurotrophic effects on DA neurons, stimulates elaboration of neuritis, and protects DA neurons from cell death.” (17). Han and colleagues found that giving L-dopa or rat mesencephalon (DA neurons) cultures increased levels of the critical antioxidant glutathione. They note: “When mixed mesencephalic cultures were exposed to strong oxidant stress….a loss of viability was seen. Cultures pre-treated with L-dopa….were protected from loss of viability.” (20). Uitti and co-workers studies survival data for all Olmsted county PD patients seen at the Mayo Clinic from 1964 to 1978. 61% of the 179 patients were levodopa-treated. They found that the treatment significantly lengthened life of PD patients compared to those not receiving the drug. “We believe our study provides compelling evidence in support of decreased mortality associated with the treatment in PD patients….Levodopa therapy improved survival unconditionally, in that it did not require early institution. We found no evidence for increased mortality in patients treated with levodopa, as one might expect hypothetically, on the basis of levodopa-related oxidative stress mechanisms.” (21).
L-Dopa : Resolving the controversy
As Murer and colleagues note, “Evidence supporting a toxic action of levodopa or DA on dopaminergic neurons arises largely from in vitro studies.” (14). More precisely, L-dopa toxicity evidence arises from one type of in vitro study – those wherein L-dopa is added to cultures containing DA neurons, but which are without glial/astrocyte cells (17, 20, 23-25). Glial/astrocyte cells are non-nerve cells that support, structurally and nutritionally, the nerve cells of the brain, retina and spinal cord (22). It is generally estimated that there are 10 times the number of glial cells than neurons in the brain. They surround nerve cells, providing mechanical support and nutritional/ antioxidant/ detoxicative/ neurotrophic services to neurons (17, 20, 26).
Mena et al. found that “In……embryonically derived glia-free (DA) neurons, …L-dopa is toxic.” (17). Han and colleagues reported that “…pure neuronal cultures (without glia) were exquisitely sensitive to the toxic effects of L-dopa.” (20). Michel and Hefti found both DA (formed from L-dopa in DA neurons) and 6-hydroxy DA (potentially formed through oxidation of DA) were potent neurotoxins to DA neurons (23). They also noted that “…our cultures contain a relatively small percentage of non-neuronal (glial) cells, and neurons are not embedded in a matrix of glial cells as in the living brain….” (23). Pardo and co-workers found that “…DA neurons are affected by L-dopa more severely, earlier, and with a lower concentration than non-DA cells.” (24). They also reported that “…our cultures….are enriched in neurons and almost (completely) lack glia (1-2% of the total population).” (24). Walkinshaw and Waters found “…that L-dopa induced death of catecholaminergic cells in vitro with an active programme of apoptosis.” (25). They also used “pure” neuronal cultures without glial cells.
Glial cells to the rescue
In contrast, many studies have used L-dopa with DA neurons combined with (“co cultured with”) glial/astrocyte cells. They have uniformly found different (and positive!) effects when L-dopa is given to DA neuron/glial combinations, which is the way neurons naturally occur in the living brain (23). Thus, Mena and co-workers found that when L-dopa was added to “dopamine neuron/cortical astrocyte (glia) cultures,” “L-dopa…protected against dopamine neuronal cell death and increased the number and branching of (neurite) processes.” (17). Mean and colleagues reported elsewhere that “L-dopa kills dopamine neurons in culture but is the most effective drug for the treatment of Parkinson’s disease, where it exhibits no clear toxicity. While glial cells surround and protect neurons in vivo, neurons are usually cultured in vitro in the absence of glia. We treated fetal mid brain rat neurons with L-dopa mesencephalic glia conditioned medium ….Mesencephalic glia therefore produced soluble factors which are neurotrophic for dopamine neurons, and which protect these neurons from the toxic effects of L-dopa.” (27). Han et al. found that “…a mild oxidative stress (generated by L-dopa) is tolerated by primary cultures of rat fetal mesencephalon (which contain both DA neurons and glial cells)….Therefore, it appears that (pure) neuronal cultures do not respond (to L-dopa) in the same way as mixed cultures, which are comprised of both neuronal and glial cells.” (20). Desagher and co-workers observed that the “…neurotoxic effect of H2O2 (Hydrogen peroxide) on neurons co-cultured with astrocytes was strongly attenuated compared with that observed on a pure population of neurons…” (26). H2O2 is a neurotoxin generated from L-dopa/DA metabolism, which may be primarily responsible for the L-dopa toxicity observed in pure (without glial cells) neuronal cultures (17, 20).
Thus, the L-dopa controversy is clearly resolved. L-dopa (and its products, DA and 6-Hydroxy DA) toxicity is an artefact. An “artefact” is an artificially produced result, “…any structure of feature produced by the technique used and not occurring naturally.” (28). The studies showing L-dopa toxicity required a specific technique: adding L-dopa (or DA/6-hydroxy DA) to neurons without glial cells. Yet in the living brain, DA neurons are naturally surrounded by glial cells, and the number of glial cells surrounding DA neurons actually increases in Parkinson’s disease, in an effort to protect the remaining neurons (17). The L-dopa toxicity studies are classic artefacts, and thus of little or no “real world” significance.
The reader is also referred back to the various studies of L-dopa in living animals and humans summarised in the section headed “L-dopa : not harmful” earlier in this article. These in vivo studies, where L-dopa interacts with DA neurons in living brains naturally “conditioned by glia”, also found not only no harm, but clear evidence of benefits to DA neurons from L-dopa.
L-Dopa neuroprotection
Although the “pure culture” L-dopa toxicity studies do not have direct application to what does on in the brain, they still have produced some interesting and potentially useful information. Although L-dopa was found toxic to DA neurons without glial protectors in these studies, it was typically found that various nutrients and pharmaceuticals could provide partial or even total protection against “L-dopa toxicity”. Thus, Han and co-workers observed that pure DA neuronal cultures were protected from L-dopa toxicity by ascorbate (Vitamin C) (20). Pardo and colleagues also reported, “In the human neuroblastoma cell line NB69, we have previously shown that co-treatment with AA (ascorbic acid) and Deprenyl, totally protected against L-dopa toxicity”. (24). Walkinshaw and Waters found that catecholaminergic PC12 cell death induced by L-dopa in glial-free culture was reduced 67% by co-treatment with vitamin E, 99% by vitamin C and 99.5% by reduced glutathione (25). Mena et al. found that both reduced glutathione, and NAC (N-Acetylcysteine), which induces intracellular glutathione production and is a direct antioxidant as well, provided major protection against L-dopa toxicity in glial free DA neuron cultures (17). Levites and colleagues discovered that the green tea polyphenol epigallocatechin-3-gallate (EGCG) provided almost total neuroprotection from 6-hydroxyDA toxicity in neuroblastoma cells (29). What these reports indicate is that any potential toxicity that might, in a worst-case scenario, somehow occur from use of L-dopa, can be prevented by appropriate nutrients and pharmaceuticals.