Gaba ?
 

I just found an old note to myself that says GABA inhibits Acetylcholine....

Does anyone know any thing about this? Would it be a good idea to take GABA for the imbalance (supposed) between dopamine and acetylcholine in PD? I can't translate the chemistry articles..

ZF? Ol'CS? Olsen?

Thanks for any insight... Ibby

High on my list of "to try"
 

GABA seems a strong possibility for the tool box. My wife (non-PD) has been taking it daily for six months or more for anxiety and it works wonders for her. Anything that counters anxiety is worth a look.

Hmm. Just went to Medline to paste in some fascinating verbage of some sort :) only to find that, for a major neurotransmitter, there has been surprisingly little done. Sigh, the profit motive strikes again.

chemical breakdowns in PD
 

Dopamine biosynthesis
The primary fault in Parkinson's disease is that, whatever the cause, there is insufficient dopamine. Dopamine is formed in the dopaminergic neurons by the following pathway:

L-tyrosine → L-dopa → dopamine
The first step is biosynthesised by the enzyme tyrosine 3-monooxygenase [1.14.16.2] (which is more commonly called by its former name tyrosine hydroxylase). The following is the complete reaction:

L-tyrosine + THFA + O2 + Fe2+ → L-dopa + DHFA + H2O + Fe2+
So for L-dopa formation, L-tyrosine, THFA (tetrahydrofolic acid), and ferrous iron are essential. The activity of this enzyme is often as low as 25% in Parkinson's disease, and in severe cases can be as low as 10%. This indicates that one or more of the elements required for the formation of L-dopa are in insufficient quantities.

The second step in the biosynthesis of dopamine is biosynthesised by the enzyme aromatic L-amino acid decarboxylase [4.1.1.28] (which is more commonly called by its former name dopa decarboxylase). The following is the complete reaction:

L-dopa + pyridoxal phosphate → dopamine + pyridoxal phosphate + CO2
So for dopamine biosynthesis from L-dopa, pyridoxal phosphate is essential. The activity of the enzyme rises and falls according to how much pyridoxal phosphate there is. The level of this enzyme in Parkinson's disease can also be around 25% or even far less.


Coenzymes involved in dopamine biosynthesis
Besides two enzymes being required for the formation of dopamine from L-tyrosine (L-tyrosine >>> L-dopa >>> dopamine), three coenzymes are also required. Enzymes are substances that will enable a specific chemical reaction to take place in the body. Coenzymes are substances that assist enzymes. Some enzymes (including those involved in dopamine biosynthesis) will not function without coenzymes.

The three coenzymes involved in the formation of dopamine are : THFA (for L-tyrosine to L-dopa), pyridoxal phosphate (for L-dopa to dopamine), and NADH (for the formation of THFA and Pyridoxal phosphate). They are made from vitamins via the following means :

Folic acid → dihydrofolic acid → tetrahydrofolic acid

Pyridoxine → pyridoxal → pyridoxal 5-phosphate (this requires zinc as a cofactor)

Nicotinamide NMN → NAD → NADH (or NADP) → NADPH


G-proteins
In order to relieve Parkinson's disease, dopamine (or dopamine agonists) must stimulate dopamine receptors, which must in turn stimulate the G proteins :

L-tyrosine → L-dopa → dopamine → dopamine receptors (D2, D3, D4) > G proteins

G proteins consist of three parts : alpha - beta - gamma, that are lined to each other. There are three types of beta unit (1, 2, 4), and seven types of gamma unit (2, 3, 4, 5, 7, 10, 11). However, they do not matter much to Parkinson's Disease. What matters to Parkinson's Disease are the alpha subunits, because it is actually these that ultimately relieve (or aggravate) Parkinson's disease. There are five types:

G proteins that aggravate Parkinson's disease : Gs 1 alpha
G proteins that relieve Parkinson's disease : Gi 1 alpha, Gi 2 alpha, Gi 3 alpha
G proteins that have little effect on Parkinson's disease : Go alpha
The sole purpose of dopamine (or dopamine agonists) stimulating dopamine receptors is to cause the alpha subunits (the active part of G proteins) to break away from the rest of the G protein. Without this occurring almost everybody would have Parkinson's disease. Once the alpha part of G proteins is released, via cyclic AMP, it takes the final action in the series of event that leads to the ridding of Parkinson's Disease, which is to inhibit the cells it has effect on.


Neuromelanin
In the cells involved in Parkinson's disease (the dopaminergic neurons) the function is to produce dopamine. In the melanocytes, which are in the skin, the function is to produce the pigment melanin. Melanin is what causes people to suntan. Although they end up with different substances (dopamine and melanin), both of these cells start off with L-tyrosine, and both of them form L-dopa as well:

dopaminergic neurons : L-tyrosine > L-dopa > dopamine

melanocytes : L-tyrosine > L-dopa > melanin

In the dopaminergic neurons, when somebody can not form dopamine, they can accidentally form melanin instead. In the brain it is called neuromelanin because of the different amino acids it is attached to. However, this is not a normal mechanism, and it occurs via a different mechanism from that found in the skin. The formation of neuromelanin in the brain is often claimed to be what happens in healthy brains. Healthy brains are supposed to be darker in the part of the brain called the substantia nigra. However, it is actually due to the biochemical mechanisms not working properly. As not much L-dopa is formed in Parkinson's disease, there isn't much capacity for that L-dopa to accidentally form melanin in the brain. So people with Parkinson's disease can tend to have not much pigment in the part of the brain called the substantia nigra. However, that does not cause a medical problem because melanin is not supposed to be in the brain.


Cell damage
The primary natural means via which cell damage can occur in Parkinson's disease is due to the reaction from L-tyrosine to L-dopa not taking place. The following is what should happen :

L-tyrosine + THFA + O2 + Fe2+ → L-dopa + DHFA + H2O + Fe2+

However, if for example, the THFA in the above reaction is lacking, the following can happen instead :

L-tyrosine + Fe2+ + O2 → L-tyrosine + Fe3+ + O-2 (superoxide anion)

As can be seen there is no L-dopa formed in the faulty reaction, and the superoxide anion is formed instead. The superoxide anion is one of the most highly destructive elements in cells. The formation of L-dopa can also fail to take place if L-tyrosine is deficient.

So the simplest means of preventing cell damage from taking place is to ensure that you have those substances required for the formation of L-dopa, which are L-tyrosine, THFA (which is made from the vitamin folic acid using nicotinamide), and ferrous iron.

Vitamin C and vitamin E have been used to try to help to prevent cell damage in Parkinson's Disease. This is because they are claimed to assist in two enzyme reactions in the brain that get rid of the superoxide anion once it has been formed :

Superoxide dismutase [1.15.1.1] : 2O-2 + 2H+ → H2O2 + O2

Catalase [1.11.16] : H2O2 → H2O + 1/2 O2

However, the problem with the use of vitamin C and vitamin E in trying to prevent cell damage is that they do nothing at all to prevent the original source of the problem, which is the formation of superoxide anion.


Lewy bodies
Lewy bodies are found in the cytoplasm of neurons. They are often depicted as cellular "rubbish bins" that collect cellular debris. So rather than being the cause of a medical disorder they are a cellular symptom, indicating that cell damage is occurring. They are composed of densely aggregated filaments. These filaments contain ubiquitin and alpha-synuclein. Lewy bodies are often associated with Parkinson's disease. However, they are not unique to Parkinson's disease, as they also occur in several other medical disorders

http://www.goldbamboo.com/topic-t160...s_Disease.html

same page ~
 

Nutrients

Nutrients have been used in clinical studies and are widely used by people with Parkinson's disease in order to partially treat Parkinson's disease or slow down its deterioration. The L-dopa precursor L-tyrosine was shown to relieve an average of 70% of symptoms.[25] Ferrous iron, the essential cofactor for L-dopa biosynthesis was shown to relieve between 10% and 60% of symptoms in 110 out of 110 patients.[26] [27] Another complementary approach is Dopavite, a nutritional supplement which contains both of these substances and all the other nutrients required for dopamine formation. However, the efficacy of this nutritional supplement has not been validated in clinical trials.

More limited efficacy has been obtained with the use of THFA, NADH, and pyridoxine—coenzymes and coenzyme precursors involved in dopamine biosynthesis[citation needed]. Vitamin C and vitamin E in large doses are commonly used by patients in order to theoretically lessen the cell damage that occurs in Parkinson's disease. This is because the enzymes superoxide dismutase and catalase require these vitamins in order to nullify the superoxide anion, a toxin commonly produced in damaged cells. However, in the randomized controlled trial, DATATOP of patients with early PD, no beneficial effect for vitamin E compared to placebo was seen[28]

Coenzyme Q10 has more recently been used for similar reasons. MitoQ is a newly developed synthetic substance that is similar in structure and function to coenzyme Q10. However, proof of benefit has not been demonstrated yet.


Physical exercise
Regular physical exercise and/or therapy, including in forms such as yoga, tai chi, and dance can be beneficial to the patient for maintaining and improving mobility, flexibility, balance and a range of motion.
http://www.goldbamboo.com/topic-t160...s_Disease.html

levesque and gaba
 

When Dr. Levesque first released information about his autonomous cell im plants [taken during a DBS and stored - later inserted - his patient showed considerable improvement symptom wise but no higher dopamine levels when measured. In an interview on GRC and Travels with Parkinson's internet radio show, Dr. Levesque was asked what he thought was causing the improvement if Dopamine levels were not increased He suspected it was GABA.

oldie but goodie, i never forgot that statement.
paula

thanks for responses everyone
 

ordered a bottle of GABA today. cheap enough. will report any and all effects. if i can figure them out. Ibby

GABA gene therapy
 

had this reference in my files:
(GABA supplements do not readily cross the BBB--perhaps an oil based one? or sublingual {under the tongue} preparation? Benzodiazapines and barbituriates stimulate GABA receptors, inducing relaxation)

Gene Therapy For Parkinson's Disease Is Safe And Some Patients Benefit, According To Study
ScienceDaily (June 25, 2007) — A novel gene therapy technique is safe and may be effective at staving off worsening symptoms of Parkinson's disease, according to the first scientific review of a dozen patients who have received the treatment over the last three years. The results were published in the latest issue of Lancet.


The patients, half of whom live on Long Island, are in advanced stages of the illness and were no longer responding to medicines when they signed on for the experimental therapy. The study was conducted by Andrew Feigin, MD, director of Neuroscience Experimental Therapeutics at The Feinstein Institute for Medical Research and his colleagues in collaboration with Parkinson's scientists at New York Presbyterian Hospital-Weill Cornell Medical Center in Manhattan.

One woman and 11 men received a surgical infusion of fluid containing a viral vector and genes for a protein called GAD, glutamic acid decarboxylase. This enzyme is critical in controlling a neurotransmitter called GABA. In Parkinson's, GABA is reduced in an area of the brain called the subthalamic nucleus. This region is working on overdrive in the disease process and GABA is an inhibitory transmitter and is important in trying to calm this hyper-reactive circuit.

The gene therapy would be used to reduce symptoms and not alter the underlying disease process. Finding novel therapies are key as many Parkinson's patients stop develop complications after prolonged use of traditional medicines.

The Feinstein's David Eidelberg, MD, took brain scans before, during and after the treatment and the scans show that the brain is re-working these abnormal circuits. Dr. Feigin said that patients had about a 27 percent improvement in symptoms, although the study was an open label design. The scientists are now designing a double-blind placebo controlled trial that would enroll far more patients in an attempt to see whether the gene therapy is effective in reducing symptoms.

The patients' scans showed a quieting of these areas, on the side of the brain where the genes were infused. The study was designed to inject the genes into one side of the brain. Normally, Parkinson's patients have worsening symptoms on one side of the body.

The novel strategy included packing genes that make an inhibitory chemical called GABA into pieces of viruses that have been rendered non-infectious. They began studying the experimental treatment in Parkinson's patients in 2003. Some patients continue to show improvement. Parkinson's patients have been willing to step up to the operating table for relief from the tremors, stiffness and rigidity that characterize the disease.

Decades ago, surgeons began to make lesions in parts of the brain involved in the disease, which lessened symptoms. Fetal stem cell surgery was pioneered in Parkinson's patients. And in the past decade, the deep brain stimulation has worked in as many as 70 percent of patients who have opted for the surgical procedure. If it doesn't work, the electrodes can be removed. (By comparison, it would be impossible to reverse gene therapy.)

"Gene therapy could be a more natural way to treat the disease," said Dr. Feigin. "This important study shows that gene therapy can be performed safely and may benefits patients."

The gene therapy technique was developed by Neurologix, a New Jersey-based company.

Parkinson's is a movement disorder caused by a progressive depletion of the brain chemical dopamine in the substantia nigra. These dopamine-containing cells control movement. When 70 to 80 percent of these cells are destroyed, a person develops the first symptoms of disease: tremors, slowed movement, muscle rigidity and problems with balance. The main medication used in Parkinson's is L-dopa, which replaces dopamine in cells that are still working normally. Over time, the cell death is so massive that the effects of the medication disappear.

Crossing the BBB
 

There's no way to know the broader picture, but I can tell you beyond any doubt that it affects my wife in a very calming way, so either it or one of its metabolites is getting through.

That brings up a point to think about. As Ron has pointed out ocassionally, :) the BBB is leaking like a sieve in PD. It would seem that things that would not cross the BBB in a healthy person just might in a PWP. So, if something looks promising but there is the barrier problem, don't make the assumption that it is useless to try.