DOPAL: possible PD trigger -- article and followup
 

The full text of this article can be found at
http://www.physorg.com/news/2011-02-...parkinson.html
for the full article please go to
http://www.physorg.com/news/2011-02-...parkinson.html

a related article
 

Parkinson's: Neurons destroyed by 3 simultaneous strikes
April 29, 2009
In a study that reveals the clearest picture to date of neuron death in Parkinson's disease, researchers at Columbia University Medical Center have found that a trio of culprits acting in concert is responsible for killing the brain cells.

http://www.physorg.com/news160228509.html

Love that last sentence -- at least it's true instead of we'll have it in five years.

" Drs. Sulzer and Mosharov are currently working on genetic therapies that could accomplish this feat, but caution that it will be years before any such treatment is ready for clinical trials, if ever."

tracking backwards to see where it begins
 

Einstein researchers discover important clue to the cause of Parkinson's disease

January 2, 2008
A glitch in the mechanism by which cells recycle damaged components may trigger Parkinson’s disease, according to a study by scientists at the Albert Einstein College of Medicine of Yeshiva University. The research, which appears in the January 2 advance online issue of The Journal of Clinical Investigation, could lead to new strategies for treating Parkinson’s and other neurodegenerative diseases.



http://www.physorg.com/news118519594.html

---------------------------------------------------

Controlling the fate of cells
July 13, 2009

Dr Jon Lane and colleagues in the University of Bristol’s Department of Biochemistry have shown for the first time that the protein Atg4D can exist in two forms. In its original form, Atg4D promotes cell survival through ‘autophagy’, a survival mechanism used by cells to overcome various environmental stresses, including starvation, and to control normal cellular processes such as growth and development
In a modified form, Atg4D can attach to the power units of the cell - the mitochondria - to stimulate cell death via ‘apoptosis’. Their research is reported in the July issue of the Journal of Cell Science.


http://www.physorg.com/news166719345.html

But this ignores some inconvenient data, doesn't it?
 

Isn't research that trumpets findings that point to the "cause" of PD as something killing neurons in the SN woefully incomplete? It ignores the 20-year head start of damage in the olfactory bulb, Braak's tracking of Lewy bodies, and who knows what else. It seems to be the same old mental cul-de-sac.

Paula: Does not this research tell us that L-dopa is toxic ?
 

I quote the following from the paper:
" The idea that dopamine contributes to the death of neurons may seem paradoxical, since most
Parkinson's patients take L-DOPA to increase the amount of dopamine inside the cells.
The new study shows that it's the location of the dopamine inside the neurons that determines its toxicity.
Most of dopamine inside the neurons is packaged into compartments that are shipped to the edge of the cell where the dopamine is released. The motor symptoms of Parkinson's arise when the amount of dopamine released by the cells declines. L-DOPA improves symptoms by boosting the amount of dopamine released by the cells. As long as dopamine is confined inside the compartments before it is released, it is safe.
New Idea for Treatment
A better treatment, the researchers say, may be to push more dopamine into the compartments where it has no toxic effect on the cell.
"
This is saying it plainly the present treatment with L-dopa is increasing Dopamine in the wrong place inside the cells which not only reduces its effectiveness but also accelerate the cell death.

Imad

yes I was trying to back track
 

This topic has been studied and debated before and the conclusion was that it was not toxic in vivo [in humans or natural setting], but was in vitro. [test tube]. Now it has come up again.

J Pharmacol Exp Ther. 2003 Feb;304(2):792-800.
Levodopa is toxic to dopamine neurons in an in vitro but not an in vivo model of oxidative stress.

Mytilineou C, Walker RH, JnoBaptiste R, Olanow CW.
Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Abstract

Levodopa is the "gold standard" for the symptomatic treatment of Parkinson's disease (PD). There is a theoretical concern, however, that levodopa might accelerate the rate of nigral degeneration, because it undergoes oxidative metabolism and is toxic to cultured dopaminergic neurons. Most in vivo studies do not show evidence of levodopa toxicity; levodopa is not toxic to normal rodents, nonhuman primates, or humans and is not toxic to dopamine neurons in dopamine-lesioned rodents or nonhuman primates in most studies. However, the potential for levodopa to be toxic in vivo has not been tested under conditions of oxidative stress such as exist in PD. To assess whether levodopa is toxic under these circumstances, we have examined the effects of levodopa on dopamine neurons in mesencephalic cultures and rat pups in which glutathione synthesis has been inhibited by L-buthionine sulfoximine. Levodopa toxicity to cultured dopaminergic neurons was enhanced by glutathione depletion and diminished by antioxidants. In contrast, treatment of neonatal rats with levodopa, administered either alone or in combination with glutathione depletion, did not cause damage to the dopamine neurons of the substantia nigra or changes in striatal levels of dopamine and its metabolites. This study provides further evidence to support the notion that although levodopa can be toxic to dopamine neurons in vitro, it is not likely to be toxic to dopamine neurons in vivo and specifically in conditions such as PD.

PMID: 12538835 [PubMed - indexed for MEDLINE]Free Article

----------------------------------------------------------
Now the possibility is being raised again.

New support for an old hypothesis: Toxic dopamine metabolites are key players in neuronal loss in PD when the intrinsic protection mechanisms fail.
By Franziska Richter, DVM, PhD, Assistant Researcher, University of California - Los Angeles


this link works fine from this search page but not from here????? so below it is the search page:

http://www.pdonlineresearch.org/resp...ayers-neuronal-

http://www.google.com/search?q=is+do...e=utf8&oe=utf8

About "Is Levodopa Toxic?"
 

The following Medscape long article concludes that L-dopa is not toxic.

http://www.medscape.org/viewarticle/433387_3

But frankly I just do not believe them because every body knows that the medical multi multy billion $ empire built on the L-dopa belief will crumble if people stop buying this belief. This is IMHO.

Imad

Toxic or not?
 

I find that whenever I look at this question and try to apply it to my experience of 8 years on l-dopa, I come up against other questions......

Not toxic?
It bought me time to bring up my son. It gave me back a lot of functionality that I was losing quite fast. Without it I become someone I do not recognise as my self.

Is Toxic?
There are side effects I don't like. These range from physical to non-motor, and the fluctuations make everything feel unreal. I should be used to them by now, but I don't think I ever will be.

Is this toxicity? I am not sure.

is it making me better or worse?
On the whole I think better.
In the long term, I don't know.

Is it killing, or maintaining my brain cells?
Neither I nor anyone else seems to be able to answer this.
The argument goes both ways, the studies show both.
I am not a scientist. My only proof is who I am.

At the moment it is still my best friend, but I am wary.
It is showing signs of being erratic, and difficult.
I am not sure when it might turn against me.

I think that is not the same thing as toxicity....
Toxic is poisonous. A killer. I do not think it is killing things.
I think it is co-opting my cells to work against me, but slowly.
Tricking me into thinking it is on my side.....
Not such a good friend as I once thought.

Lindy:
 

I appreciate every word you say and I take myself a low dose of sinemet. My rage at L-dopa solution to PD is my belief that it is used by neuros as a false fix to the problem which side tracked efforts for finding better healing in the last 50years.
Imad

Imad,
I don't think it was a false fix, I think it was their only fix for a while. It will be at some time in the future regarded as a helpful drug that kept peopple going for a while.

Having said that, I have to look at the wonderful results of duodopa that are reported..... so cannot condemn it.

Whatever drug is giving us back our lives is good.
When it starts taking away our lives it becomes a lot less than good.

In the meantime all the bright ideas do not seem to translate into treatments.
They get stuck in the pipeline, languish there, and often disappear.

I like Paula's idea's about medication.
Not for profit pharmaceuticals.
If there was a will, a way appeared.
as yet the will is not there.

In the meantime even the doctors are not really that sold on l-dopa.
They are trying, a lot of them. And thinking hard too.

I don't think that l-dopa really side tracked the good doctors.
It was always fraught with difficulties from the beginning.
Until carbidopa, then they thought maybe...
then dyskinesias, then they thought again.

It is not the doctors that are the real problem,
It is the pharmaceutical industry wanting profits over cures.
It is the regulatory processes being incredibly slow.
It is the media saying that every little development is a 'cure'.
It is the incredible cost of everything from medication to mice.
It is the arcane processes of trial design.
It is the inability of science to maintain dialogue with citizens.

Overcome these and you will find better healing right across the board.

But you are right to make a noise anyway!! :winky: