The Understood Cellular Causes of Parkinson’s Disease (PD) and Treatments

[See Testimonial (below the following outline) of the rigorous routine of an individual who completely reversed her Parkinson’s Disease with natural means, and also see there the tissue-targeted treatments employed by a Neurologist.]

To start, I will take you from the outside to the inside of the brain showing areas of damage, and then list treatments to address the cellular causes of PD.

Here is the outside of the brain showing where the damage primarily occurs in Parkinson’s Disease: The Substantia Nigra:

Parkinson’s Disease primarily the SN

Here, in the Substantia Nigra (SN), PD causes damage to Dopamine cells (Neurons) and the surrounding Microglia (supporting cells): This is the basis for the electronic implants that some doctors will use that provide signals to this area that can help lessen the symptoms of PD.

Going deeper into the peri-cellular level in the picture below, you can see that what you eat is important to the health of the dopamine cell as what you ingest either supports or damages the SN supporting glial cells and the dopamine cells. 

Blood flow components flow easily from the capillaries to the glial cells & dopamine nerve cells (damaging can take the form of inflammatory foods, pesticides, heavy metals or other toxins) and support is for your diet to cause the supporting glial cells to secrete “GDNF”–A growth factor for the dopamine cell.


However, in PD, these glial cells can become “inflamed” and when that happens, they damage the health of your dopamine cells.  The area most injured in PD is the Substantia Nigra, produces a lot of free radicals, or inflammation, and also happens to be poorly supplied with free radical defenses. Therefore, we have our first abnormal finding for reasonable treatment: First, identify and remove food allergens, environmental allergens, and chemicals that may be inflaming these cells. Then increase free radical defense systems.  

There is a long list of possible inflaming substances you might ingest towards the end of this page.


This picture, below, shows the dopamine cell as it begins to be injured.  The arrows point to the “branches” of the cell that are partially damaged: The fact that many cells are only partially damaged is great news–You may be able to rescue these partially damaged cells and regain function as they regain their health and function. 


It is the lowering of dopamine levels from the loss of functioning of the dopamine cells which is why the first line of treatment from a conventional doctor is usually aimed at increasing the dopamine in your brain–either directly with “L-Dopa” or indirectly with “Dopamine Agonists (drugs that stimulate the cell’s production of dopamine).

Increasing dopamine requires a careful balance of “healthy” and “unhealthy” levels of dopamine– too much dopamine can worsen your inflammation, or free radical imbalance, inside the cell and out in the synapse (the area where the cell dumps its dopamine.)    

Here is the dopamine in the “synapse,” or area between the brain cells. First, the dopamine attaches to, and signals the cell next to it, and then the dopamine is taken back into the original cell to break it down.


If there is too much dopamine in this synapse, and the cell cannot break it down well enough, inflammation starts to occur as “free radicals” start to damage tissues. Dopamine can hurt the nerve endings (“auto-oxidation”) and can overwhelm the cells ability to respond to the increase in re-absorbed dopamine. This is why it is important that you understand the effects of any drugs, supplements, or herbs that you are consuming that effect dopamine levels.         

Here is the inside of the cell where damage begins in Parkinson’s:         

Looking at the “organelles” inside the cell, we see more abnormalities that can serve as the basis of treatments:

First, there is a problem at the pink structure above, the “endoplasmic reticulum,” called “ER Stress,” that results in problems with protein folding.  Therefore, one  rational treatment strategy is reducing “ER Stress.”

Second, there is “clumping of alpha-synuclein” that includes misfolded proteins, especially at the nerve terminals (endings). alpha synuclein (alpha-syn) is a constituent of filamentous Lewy bodies (LBs) and Lewy neurites (LNs) in Parkinson’s disease (PD).1–3 Three missense mutations in the -syn gene as well as gene duplications/triplications have been reported in familial PD with or without dementia.

Accumulation of misfolded proteins due to a variety of stress situations leads to up-regulation of heat shock proteins (Hsps) to facilitate refolding and prevent aggregation of misfolded proteins.20,21 Hsps may help ubiquitinate and target nonrepairable proteins to the proteasome.22 Although proteasome impairments are linked to the formation of inclusions in neurodegenerative disorders, including PD,  Hsps can also be induced by proteasome inhibitors.  Various Hsps have been found in cytoplasmic inclusions of neurons and glia in diverse neurodegenerative diseases Hsp90 is an abundant molecular chaperone that prevents protein aggregation and increases Hsp expression.30 Although it has an ATPase domain, Hsp90 can act independently of ATP and can prevent protein aggregation alone or with other chaperones, such as Hsp70.30 Although several studies suggest Hsp70 plays a mechanistic role in alpha-synucleinopathies, Hsp90 has been demonstrated to be the dominant Hsp involved in alpha-synucleinopathies.

Getting rid of α-synuclein uses the lysosomal pathways of chaperone-mediated autophagy (CMA) and macroautophagy (Paxinou et al. 2001; Webb et al. 2003; Cuervo et al. 2004; Lee et al. 2004; Vogiatzi et al. 2008; Mak et al. 2010). It has been proposed that dysfunction of these degradation pathways may be a contributing factor to Parkinson’s Disease. (Xilouri et al. 2008).  Hsps can also be induced by proteasome inhibitors.

Therefore, another rational treatment strategy will include trying to improve CMA and macroautophagy so the cell can get rid of the alpha-synuclein. 

α-Synuclein may also be turned over by the proteasome in other experimental settings (Tofaris et al. 2001; Webb et al. 2003). Therefore, another rational treatment strategy is to reduce proteasome dysfunction. 

PD induces mitochondrial (the cell’s “batteries) damage, with too many free radicals being released with damage to not only the mitochondria, but also other parts of the cell.  

The mitochondria is damaged in the electron transport chain (ETC) at Complex I (and to a lesser extent, Complex III) :

Present research suggests that Complex I (the purple structure), is one of the first structure to stop working properly, (Schapira et al., 1989, 1990)  and begins releasing too many damaging “free radicals” in a part of the brain that seems to have insufficient free radical defenses.  NADH, which supplies Complex I, is also found to be abnormal in this area of the mitochondria. Therefore, a rational treatment strategy will include treatment to increase function of Complex I, while also treating the conditions that may be causing this Complex to reduce its function in the first place 

So we have identified problems in the brains of Parkinson’s Disease that we can treat properly in a rational, tissue-targeted approach:

 1. Restore the brain’s protective antioxidants with intravenous, subcutaneous, and/or oral approaches. Dr. Perlmutter has been a pioneer of the use of intravenous glutathione, a powerful antioxidant, for his patients with Parkinson’s Disease and also has produced “Brain Sustain,” a nutritional product to support brain cell health. Maximize the blood’s free radical defences–For instance, increasing your Uric Acid to the high normal level. (Uric Acid has been reported to  be able to neutralize up to 60% of blood free radicals,.)

2. Identify and reduce the excessive free radicals, or *inflammation.” Avoid circumstances that produce large number of free radicals in the body.   Avoid unnecessary x-radiation and exposure to microwaves. If your doctor recommends a cat scan, make sure it is really necessary. And if you do have to have a cat scan, fluoroscopy or other intensive X-ray procedure, load up on antioxidants before and after the event.  Absolutely do not smoke and avoid breathing second-hand smoke. Do not use tanning booths.  Avoid exposure to heavy metals and toxic chemicals. Do not consume liquids that are in plastic bottles that have been frozen or overheated, such as water bottles baked in a car in the summer sun.  Avoid situations likely to lead to infections.  Wash your hands frequently; many infections are communicated by touch. Avoid unnecessary stress, be it physical, circumstantial or emotional.  Too vigorous exercise can be harmful.

Learn how to avoid exposure to beta-carbolines and isoquinolones, from food as well as from Candida infections. Check for “silent” food allergies and allergies of any other kind. You can use Hydroxy-B12 to bind excessive superoxide free radicals. (Use after heavy meals.)

Reducing free radicals reduces NF-kappaB, and that allows your nerve cells to grow. Research has shown that the following promote neurogenesis: DHEA, pregnenalone, resveratrol, curcumin, Ginkgo bilboa and EPA fish oil

3. Consider dietary changes and supplements that will decrease the unfolding protein response of proteins within the endoplasmic reticulum that suffer from “ER Stress.” See Appendix below.

Consider a “ketogenic diet.” 

Ketones are a special type can stimulate the pathways that enhance the growth of new neural networks in the brain. A ketogenic diet is one that is high in fats, and this diet has been a tool of researchers for years, used notably in a 2005 study on Parkinson’s patients which found an improvement in symptoms after just 28 days. The improvements were on par with those made possible via medication and brain surgery. Ketones do more than just that though. They increase glutathione, a powerful, brain-protective antioxidant, levels in the hippocampus. Ketones facilitate the production of mitochondria, one of the most important actors in the coordinated production that is the human body.of fat that 

– See more at\\on YouTube video lectures on a ketogenic diet.

4. Help restore the function of the damaged Complexes I with Coenzyme Q10 and NADH. Enzyme function of NADH ubiquinone reductase in the platelets of Parkinson’s disease patients is noted to be 30-60% lower than that of aged match controls. This activity increases following administration of NADH. Birkmayer has demonstrated improvements of short-term memory and other cognitive functions in Parkinson’s patients treated with NADH.

5. Reduce the increased iron seen in association with alpha-synclein in Parkinson’s, as well as chemical toxin load– Especially, the pesticide load in the body. See Dr. William Rea’s books on the “body burden” of toxins leading to diseases.

6. Reduce “vicious cycles” of cell damage. One of these is calcium dysregulation: Learn how to block the excessive “triggering” of damaging, excessive release of calcium within the cell. Another is OONO- generation. See Dr. Pall’s protocol.

7. Use dietary patterns with the awareness of the cellular natural circadian rhythms to maximize lysosomal and macroautophagy disposal of alpha-synuclein.

8. Go over the risks and benefits of replacing dopamine to compensate for the decreased levels from the cell damage in the Substantia Nigra. A gentle way is to take the amino acid L-Tyrosine, the building block for dopamine. An extremely complex area is the use of L-Dopa for greater increases in cell dopamine. The “Life Extension” website has an extremely thorough review of considerations on taking L-Dopa for Parkinson’s Disease.

8. Consider the use of some of Annetta Freeman’s tools outlined below

How to Reduce Endoplasmic Reticulum Stress:

This includes reducing activation of the JNK pathway, NFkB, and cytokine production. Reduce acrolein levels. (Reference: Toxicology and Applied Pharmacology Volume 234, Issue 1, 1 Jan 2009, Pages 14-24  Role of endoplasmic reticulum stress in acrolein-induced endothelial activation Petra Haberzettla, Elena Vladykovskayaa, Sanjay Srivastavaa and Aruni Bhatnag  aInstitute of Molecular Cardiology U of Louisville

“Acrolein is a ubiquitous environmental pollutant and an endogenous product of lipid peroxidation. It is also generated during the metabolism of several drugs and amino acids…. Acrolein-induced increase in (changes of ER Stress) were prevented by treating the cells wth the chemical chaperone — phenylbutyric acid (PBA). Treatment with acrolein increased the JNK pathwauy, NF-κB nuclear trannlocation, and an increase in cytokine productioon. Increased JNK pathway, expression of cytokine genes and NF-κB activation were not observed in cells treated with PBA. These findings suggest that exposure to acrolein induces ER stress and triggers the unfolded protein response and that NF-κB activation and stimulation of cytokine production by acrolein could be attributed, in part, to ER stress. Chemical chaperones of protein-folding may be useful in treating (ER Stress) associated with excessive acrolein exposure or production.”

Addendum 1: Medications

There have been many remarkable changes in treatments for Parkinson’s disease in recent years. Scientists have developed new drugs, and they have a better understanding of how to use older treatments. That has made a big difference in everyday life for people with the disease.

Most people can get relief from their Parkinson’s symptoms with medicines. But some may need surgery if their medications stop working well enough.

The medicines you take early on have a strong impact on how your condition will unfold over time. So it’s important to work with a neurologist or other Parkinson’s specialist who can guide you through those treatment decisions.

Common Drugs for Parkinson’s Disease

Levodopa and carbidopa (Sinemet). Levodopa (also called L-dopa) is the most commonly prescribed medicine for Parkinson’s. It’s also the best at controlling the symptoms of the condition, particularly slow movements and stiff, rigid body parts.

Levodopa works when your brain cells change it into dopamine. That’s a chemical the brain uses to send signals that help you move your body. People with Parkinson’s don’t have enough dopamine in their brains to control their movements.

Sinemet is a mix of levodopa and another drug called carbidopa. Carbidopa makes the levodopa work better, so you can take less of it. That prevents many common side effects of levodopa, such as nausea, vomiting, and irregular heart rhythms.

Sinemet has the fewest short-term side effects, compared with other Parkinson’s medications. But it does raise your odds for some long-term problems, such as involuntary movements (dyskinesia’s).

Adamas Pharmacy is bringing to market it’s lead product GOCOVRI which is indicated for treatment of dyskinesia’s (involuntary and non-rhythmic movements that interfere with daily living) in patients with Parkinson’s disease receiving levodopa-based therapy. Neurocrine is also bringing Ongentys (opicapone) to market for dyskinesia’s and Teva Pharmaceutical’s offers  AZILECT (rasagiline tablets) as monotherapy, adjunct to levodopa (LD) or adjunct to dopamine agonists (DAs) for either dyskinesia’s or as monotherapy. 

People who take levodopa for 3-5 years may eventually have restlessness, confusion, or unusual movements within a few hours of taking the medicine. Changes in the amount or timing of your dose will usually prevent these side effects.

Dopamine agonists. These drugs act like dopamine in the brain. They include ropinirole (Requip), pramipexole (Mirapex), and rotigotine (Neupro).

You can take one of these drugs on its own or along with Sinemet. Most doctors prescribe dopamine agonists first and then add levodopa if your symptoms still aren’t under control.

Dopamine agonists don’t have the same risks of long-term problems as levodopa therapy. So they are often the first choice of treatment for Parkinson’s disease.

However, these drugs do raise the chances of some short-term side effects, such as nausea, vomiting, dizziness, light-headedness, confusion, and hallucinations.

Amantadine (Symmetrel) may help people with mild Parkinson’s disease.

It works by raising the amount of dopamine that your brain cells can use, which helps you have fewer Parkinson’s symptoms. Recent studies have found that Symmetrel may help ease the involuntary movements that can happen with levodopa therapy. But it may cause side effects, such as confusion and memory problems.

Trihexyphenidyl (Artane ) and benztropine Cogentin). These drugs restore the balance between two brain chemicals, dopamine and acetylcholine. That eases tremors and muscle stiffness in people with Parkinson’s. But these medications can harm memory and thinking, especially in older people. Because of that, doctors rarely prescribe them today.

Selegiline (EldeprylZelapar) and rasagiline (Azilect). These drugs block the brain chemicals that break down dopamine. That helps your brain have more dopamine to work with.

Some evidence shows that selegiline may slow the progression of Parkinson’s disease, especially early on. Common side effects include nausea, dizziness or fainting, and stomach pain.

Studies of animals suggest that rasagiline may also slow the progression of Parkinson’s. Side effects include headachejoint painindigestion, and depression.

Tolcapone and entacapone. When you take levodopa, a chemical in your body called COMT makes part of the drug useless. The drugs tolcapone (Tasmar) and entacapone (Comtan) block COMT, so the brain can use levodopa more effectively, which eases Parkinson’s symptoms.


Addendum 2: Testimonial supporting a non-medication routine that reversed Annetta Preeman’s  PD

An Improved Parkinson’s Therapy

by Steven Wm. Fowkes

For years, we have been discussing the use of deprenyl in the treatment of Parkinson’s disease and the use of antioxidants for the treatment of free-radical pathologies and aging. Now, Annetta Freeman, a 58-year-old housewife from Beverly Hills, California has put the two together with phenomenal results. In 1992, she was almost completely disabled by Parkinson’s disease, today she is largely recovered. She says “When I walk into a room today, no one would guess that I had Parkinson’s disease.”

Annetta Freeman’s Personal Regimen for Parkinson’s Disease

Compare this regimen to her updated regimen three years later.

Liquid deprenyl citrate (1 mg/drop)
10 drops (3 morning, 2 noon, 3 early afternoon, 2 late afternoon)

DHEA (50 mg)
1 every other morning

Vitamin E (1000 IU)
1 each morning, noon and evening

Vitamin C (L-ascorbic acid powder)
approx. 1500 mg each morning and evening

Cell Guard (antioxidant enzyme)
5 tablets each morning for two weeks
3 tablets each morning thereafter

Vitamin A/D (25000 IU/1500 mg)
1 tablet each morning

Sun Chlorella A
5 tablets each morning, noon and evening

Coenzyme Q10 (30 mg)
1 each morning and evening

Viobin Prometabs (5 g octacosanol)
1 each morning and evening

L-Glutathione (50 mg)
1 each morning

Pycnogenol (50 mg)
4 each morning and evening

For My General Health:

GLA-125 (600 mg) [gamma linolenic acid]
1 each morning and evening

Ginkgo biloba (40 mg)
1 each morning and evening

MaxEPA (1000 mg omega-3 EPA) [eicosapentaenoic acid]
1 each morning and evening

B-complex 100
1 each noon (don’t take if you take Sinemet!)

Potasium and Magnesium
1 each morning and evening

1 each morning

Maxi L-carnitine (500 mg)
1 each morning

Chromium picolinate (200 mg)
1 each morning

Cayenne Power Caps Hot
1 each morning and evening

B-12 injections
once weekly

Flax oil
(1 tbsp in 4 tbsp cottage cheese)

Melatonin (9 mg)
evening only

UPDATED REGIMEN 3 years later

Discovery-brand Liquid Deprenyl Citrate
3 mg morning, 2 mg noon, 3 mg early afternoon, 2 mg late afternoon (adjust timing for smoothest effect, avoid taking with NADH).

50 mg (every other morning).

Vitamin E†§
1000 IU (with breakfast, lunch and dinner).

Vitamin C (L-ascorbic acid)
1500 mg in morning, same in evening (OK to take with or without food).

Kyo Green
2 tbsp in morning (a barley green product, replaces Cell Guard).

Vitamins A and D
25,000 IU A and 1500 mg D (with breakfast).

Sun Chlorella A
5 tablets with breakfast, 5 with lunch and 5 with dinner (a broken-cell-wall green algae, not a blue-green algae product).

Coenzyme Q-10
Four 30 mg caps, 2 with breakfast, 2 with dinner (mitochondrial energy enhancer).

Viobin Prometabs† (5 mg octacosanol)
One tablet with breakfast and dinner (a grain concentrate, special order from health food stores).

50 mg in the morning (an important cellular antioxidant).

Four 50 mg capsules in morning & evening (less expensive grape seed extract contains similar antioxidants).

Enada (NADH, coenzyme 1)
Two 5 mg tablets first thing in the morning (some people take it before bed).

Alpha-Lipoic acid
50 mg in morning, same in evening (mitochondrial enhancer, new to program, decreases morning stiffness).

Acetyl-L-Carnitine (ALC)
One 500 mg tablet each morning (mitochondrial energy enhancer, new to program, replaces L-carnitine).

B-complex “100”
One with lunch (do not take if you take Sinemet!).

B-12 Injection
Once weekly (now with folic acid).

At least 8 glasses per day (take a full glass when taking supplements).

GLA-125 (gamma-linolenic acid)§
One with breakfast and dinner.

MaxEPA§ (1000 mg)
One capsule with breakfast & dinner (omega-3-rich cold-water fish oil).

Flax oil§
One tbsp in 4 tbsp cottage cheese.

Multi-mineral tablet
One tablet with breakfast.

Potassium and magnesium
One tablet each morning and evening (300 mg magnesium, 90 mg potassium).

Chromium Picolinate
200 mcg in morning (blood sugar stabilizer).

Cayenne Power Caps (Hot)
One each morning and evening.

Three 3 mg tablets before bed (dosage must be individually adjusted).

1 gram with one aspirin before bed (minimizes twitching and pain, reduces shaking the next morning and helps me sleep “like a baby” all night).

Gingko biloba (40 mg)
One tablet each morning and evening.

Betaine hydrochloride
With meals, as needed (increases stomach acidity, aids digestion, improves nutrient absorption).

Flora Source
2-30 minutes after eating (Golden Health Products 217-696-2378).

Aloe Gold
1/3 to 1/2 glass with cranberry juice (takes more when eating allergenic foods).

Mild silver protein
1/4 tsp (a general prophylactic against illness).

Notes and Comments
I consider these items most important for Parkinson’s, non-daggered items are for my general health.
Steven Fowkes thinks that 100 mgs of each B vitamin is a faulty formulation (B-3 and B-5 doses need to be more; B-1, B-2 and B-6 can be much less). Because B-complex nutrients are water-soluble and have short half-lives, he suggests taking them in divided doses with each meal instead of once at lunch.
§ Polyunsaturated fatty acids can go rancid quite easily. Even the vegetable oils added to vitamin E pearls can rancidify easily. These products should be taste tested once a week to make sure they are still fresh. Rancidity produces a bitter and acrid taste/flavor in the back center of the tongue. It may also produce a gaging reflex.

Many of these medications try to lessen inflammation and oxidation of the cell, and instead provide antioxidants and other substances that might restore the health of the dopamine and glial cells.

Dr. Tipi Siddique from Northwestern University had written an article about a gene that he had discovered that was faulty in ALS and Parkinson patients. It was a gene that produces antioxidants.

Which did you try and which ones do you consider were most helpful?

I don’t think that there’s one product I can single out. The Pycnogenol has been a godsend and I cannot lower my dose, even today. Also, the Cell Guard must be considered a mainstay of the program.

I’ve had various doctors suggest that I try to eliminate one or more antioxidants and see the result. I’ve tried that and I did not do well. So I think the benefits I am getting are from the combination of the ones that I’m taking. I think the most important ones are vitamin C, vitamin E, the Cell Guard (which increases the SOD level in the body), the Pycnogenol (which magnifies the C and E), the glutathione (which everybody tells me can’t do a thing but it does), and a product that I never thought could help, Sun Chlorella.


Other Queries: 

How Can I Test For My Antioxidant Stress?          

Measuring lipid peroxides could prove to be a very helpful marker in Parkinson’s. This is done with a sample of urine taken first thing in the morning. Unfortunately, there are several kinds of oxidative stress and insufficient clinical testing for each of these. 

As you recall, inflammation from foods (allergies, imbalanced fats, oxidized cholesterol, etc), microbes in your body, chemicals, heavy metals and other sources produce Free Radicals: There are also dysfunctional–possibly injured or genetically impaired–parts of the mitochondria that may be addressed with treatments.

The relatively new awareness in the research community on the central role of free radicals in Parkinson’s Disease is obvious by the huge volume of recent research papers on this subject. 

In PD, there may be other intracellular structures which release too  many free radicals, damaging the inside of the cells. (Complex III releases too many free radicals and the increased NADH/NAD+ ratio causes the alpha KGDH enzyme to release too many free radicals.)  Finally, the excessive free radicals may damage the mitochondrial DNA–activating calcium cascades that injure the cells. 


Sophisticated Science for those interested…

A free radical is an atom which had an odd number of electrons in its outer ring so that one of the electrons is unpaired, unstable and “unhappy.”  Below you can both see the “free radicals,” but also how they attack the cell and the cell membranes.    



NADH plays a pivotal role in the function of complex I of the respiratory chain. Enzyme function of NADH ubiquinone reductase in the platelets of Parkinson’s disease patients is noted to be 30-60% lower than that of aged match controls. This activity increases following administration of NADH.

Birkmayer has demonstrated improvements of short-term memory and other cognitive functions in Parkinson’s patients treated with NADH. This report is not accepted by some, who doubt oral NADH can significantly increase the NADH needed in the injured cells of the brain. It is sold in sublingual form to bypass the digestive system to attempt to raise levels.     

During excessive free radical production, it is important to lessen the energy crisis in the cell (dysfunctional mitochondria’s) to help save the dopamine cells so you can function better. NADH, Niacinamide and others may be able to help with the energy crisis. See my tab on the homepage on increasing mitochondrial function and cell energy.  

The other free radicals sources include NAD(P)H and the cytochrome activity during the night and:

1) Inhibition of Complex I via DHBT-1 from the cell breaking down “used” dopamine.

 2) Dopamine breakdown product: 5-S-CyS-DA to DHBT-1: DHBT-1 inhibits Complex I, (but not Complex II) and aKGDH Complex

Oxidative metabolites of 5-S-cysteinyldopamine inhibit the α-ketoglutarate dehydrogenase complex : possible relevance to the pathogenesis of Parkinson’s disease Journal of neural transmission   SHEN X.-M. et al. 2000, vol. 107, no8-9, pp. 959-978  Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK, A characteristic change in the substantia nigra of Parkinson’s disease patients is an apparent accelerated rate of dopamine oxidation as evidenced by an increased 5-S-cysteinyldopamine (5-S-CyS-DA) to dopamine ratio. However, 5-S-CyS-DA is more easily oxidized than dopamine to give 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1). Previous studies have demonstrated that DHBT-1 can accumulate by intact rat brain mitochondria and inhibits complex I but not complex II respiration.

In this study, it is shown that DHBT-1 also inhibits the α-ketoglutarate dehydrogenase complex (a-KGDH) but not cytochrome c oxidase (complex IV). The inhibition of α-KGDH is dependent on the oxidation of DHBT-1, catalyzed by an unknown constituent of the inner mitochondrial membrane, to an electrophilic o-quinone imine that covalently modifies active site sulfhydryl residues. The latter conclusion is based on the ability of ≥ equimolar glutathione to block the inhibition of α-KGDH by DHBT-1, without altering its rate of mitochondrial membrane-catalyzed oxidation, by scavenging the electrophilic o-quinone intermediate forming glutathionyl conjugates which have been isolated and spectroscopically characterized. Activities of mitochondrial α-KGDH and complex I, but not other respiratory complexes, are decreased in the Parkinsonian Substantia Nigra.

Such changes together with evidence for accelerated dopamine oxidation, increased formation of 5-S-CyS-DA and the ease of oxidation of this conjugate to DHBT-1 which inhibits α-KGDH and complex I, without affecting other respiratory enzyme complexes, suggests that the latter putative metabolite might be an endotoxin that contributes to the α-KGDH and complex I defects in Parkinson’s disease.

3)  Chemicals (which can be related to certain foods and Candidiasis) such as Isoquinolones (IQs) and Beta Carbolines are neurotoxins which have been found in the brain of PD (Nagatsu, 1997)

Catecholamines (DA, NE, E) are converted by MAO, and the aldehydes may undergo a Pictet-Spengler type of condensation to yield 1,2,3,4-tetrahydroisolquinolines (TIQs), such as tetrahydropapaveroline (norlaudanosoline) [Davis and Walsh, 1970; Cohen and Collins, 1970; Zarrang and Ordonez, 1981] TIQs are present in cheese, banana, broiled sardine and beef, flour, yolk and white of egg, milk, beer and whiskey.

Here is a picture of how free radicals (red) disrupt the brain cell membranes–“kinking” them:      

Hydroxyl radicals (OH•) damage membrane lipids and proteins by removing H atoms from the lipid chains and from protein sulfhydryl groups (SH). The structure of both lipids and proteins is disturbed.

Some neurons in the brain are more susceptible to oxidative damage than others. Those neurons that contain dopamine and other oxidizable neurotransmitters, such as serotonin, are quite vulnerable.

Oxidative damage (caused by any means) in different parts of the brain can produce different neuro­logical effects. For example, dopamine neurons are found in pathways that control voluntary move­ment. Oxidative damage to dopamine neurons in these pathways can cause movement problems. Simi­larly, movement disorders are associated with Parkinson’s disease, in which dopamine neurons degenerate within an area of the brain called the basal ganglia. The basal ganglia are important in maintaining voluntary movement; degeneration within these structures results in trem­ors and tics.

Older vs Newer Treatments: “Shotgun approach” versus the Tissue-Targeted Approach ANTIOXIDANTS

Free radicals are the result of oxidative damage or oxidative stress, and are believed to play a leading role in certain diseases and age-related changes. Although the body also produces antioxidants, over time, production declines. Free radical destruction is thought to be a contributing factor to the decline in memory and motor performance seen in aging.

Brain cells are at particular risk of being damaged by free radicals because the brain has a high oxygen turnover, and CNS neuronal membranes are rich in polyunsaturated fatty acids, which are potential targets for lipid peroxidation. (Endocrinology, 1997 Vol 138, No. 1 p101-106) In addition, the brain is relatively deficient in antioxidants.

Free radicals and oxidative stress-induced neuronal cell death have been implicated in various neurological disorders, such as Parkinson’’ disease and Alzheimer’s Disease.

The well documented fact that one major change in the CNS that is associated with aging is free radical-induced oxidative damage.

Ames BN 1993 Oxidants, antioxidants, and the degenerative diseases of aging. (Proc Natl Acad ) 90:7915-7922

Vegetables are key sources of antioxidants.

(The Journal of Neuroscience October 1998;18.)

A diet rich in vegetables may help prevent age-related mental decline. Investigator’s results show that vegetables, particularly spinach, may be beneficial in retarding age-related central nervous system and cognitive behavioral deficits

Supplements that work as antioxidants.

(Int J Biochem Cell Biol 2001 May;33(5):475-82)

Vitamin E, beta-carotene and N-acetylcysteine protect the brain from oxidative stress induced by lipopolysaccharide (LPS, endotoxin). Administration of the aforementioned antioxidants prior to LPS injection ameliorated the oxidative stress by reducing levels of MDA, restoring GSH content and normalizing the mitochondrial/cytosolic hexokinase ratio in the brain in addition to lowering levels of plasma corticosterone and glucose

Dr. Perlmutter’s Supplements

Vitamin E Of the various types of chemicals found within the body, fat is the most susceptible to being damaged by free radicals. This explains why the brain, having such a high content of fat, is at such an increased risk for free radical damage. Vitamin E is a “fat soluble” antioxidant meaning that its protective effect is most realized in tissues with a high fat content–like the brain. This explains why vitamin E has been so extensively studied in such brain disorders as Parkinson’s disease and Alzheimer’s disease. It is vitamin E’s profound ability to limit the damaging action of free radicals in the brain that likely explains why it outperformed a so called “Alzheimer’s drug” in a clinical trial of Alzheimer’s patients in a 1997 report in the New England Journal of Medicine.1 Indeed, diets rich in natural sources of vitamin E are associated with a reduction in the risk of Parkinson’s disease by an incredible 61%.2 In individuals already given the diagnosis, the progression of Parkinson’s disease has been dramatically slowed with vitamin E and C supplementation.3

Gingko biloba Like vitamin E, Gingko biloba, has potent antioxidant activity. It also directly improves brain metabolism and increases brain blood flow. Gingko biloba is clearly one of the most extensively studied nutritional supplements, especially in neurodegenerative conditions. In a placebo-controlled, double-blind randomized trial published in the Journal of the American Medical Association, not only did Gingko biloba stabilize Alzheimer’s disease, but in many of the subjects there was an actual improvement noted in various standardized psychological tests.4

Coenzyme Q-10 Coenzyme Q-10 plays an important role in the critical process of cellular energy and is found in every living cell of every living being. In addition, it serves an important role as a brain antioxidant. When administered orally it is readily absorbed and measurably increases the efficiency of cellular energy production as demonstrated in studies performed at the Massachusetts General Hospital.5 This explains why Coenzyme Q-10 is being vigorously evaluated at major institutions around the world as a therapeutic aid in brain disorders. Interestingly, Parkinson’s disease patients demonstrate dramatically lowered levels Coenzyme Q-10 which may in part explain why these patients experience higher levels of brain damaging free radical activity.6

Alpha Lipoic Acid This powerful antioxidant is the subject of intensive worldwide study in neurodegenerative diseases because of its powerful antioxidant activity as well as its ability to regenerate other important brain antioxidants including vitamins E, C, and glutathione. Unlike other antioxidants, alpha lipoic acid is both fat soluble and water soluble. This greatly enhances its ability to be absorbed from the gut and permits increased penetration into the brain.7

N-Acetyl-L-Cysteine (NAC) While glutathione represents one of the most important of the brain’s antioxidant’s defenses, it is generally considered useless when given orally. NAC is readily absorbed from the gut and dramatically increases the body’s production of brain protecting glutathione. The ability of NAC to increase brain glutathione is enhanced in the presence of adequate amounts of vitamin C and E. In addition to enhancing glutathione production, NAC itself is a potent antioxidant and has been demonstrated to reduce the formation of the free radical nitric oxide which has been implicated as having a causative role in Parkinson’s disease, Alzheimer’s disease, and several other neurodegenerative disorders.8

Acetyl-L-Carnitine Damaged brain neurons are characterized by a decreased ability to produce energy. Like coenzyme Q-10, acetyl-L-carnitine enhances neuronal energy production by functioning as a shuttle–transporting fuel sources into mitochondria, the energy producing machinery of the neuron. It also assists in removing toxic by products of brain metabolism and acts as a potent antioxidant. Acetyl-L-carnitine has been demonstrated to protect laboratory animals from developing full-blown parkinsonism when exposed to specific chemicals know to induce the disease.9 It has been extensively studied in Alzheimer’s disease and, as reported in a recent issue of the journal Neurology, acetyl-L-carnitine can profoundly reduce the rate of progression of Alzheimer’s disease in younger patients.10

Phosphatidylserine Research carried out at Stanford University evaluating 149 patients suffering from dementia demonstrated that orally administered phosphatidylserine produced a marked improvement on performance tests related to memory and learning in demented patients.11 Like acetyl-L-carnitine and coenzyme Q-10, phosphatidylserine plays an important role in maintaining the ability of brain neurons to produce energy. Phosphatidylserine is a fundamental component of the fatty membranes surrounding the mitochondria where energy production occurs. In addition, it also serves as a critical component of the membrane surrounding neurons and thus plays a fundamental role in the process by which brain cells both receive and transmit chemical messages.

Vitamin D Deficiencies of vitamin D have been found in Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease. It is only in the past several years that vitamin D has been recognized as having far more important role in human health than simply aiding bone formation. Vitamin D is now recognized as a potent fat-soluble antioxidant. Several studies have indicated that vitamin D’s ability to quench free radicals is even more powerful than vitamin E.12

Vitamin B12 (Cyanocobalamin) Deficiency of vitamin B12 has been associated with mental slowness, confusion, depression, memory difficulties, abnormalities of nerve function, Alzheimer’s disease, and multiple sclerosis. Not only is vitamin B12 critical for the maintenance of myelin, the protective insulating coat surrounding each neuron, but it also helps reduce the level of a particular amino acid, homocysteine, which has been associated with increased risk for Alzheimer’s disease, stroke, and myocardial infarction.

Magnesium This important mineral is critical in a program designed to preserve and enhance brain function for several important reasons. First, adequate amounts of magnesium are necessary for the electrical depolarization of the neuronal membrane. This is the process by which chemical messages are transmitted from one neuron to the next. Next, magnesium enhances the function of various brain antioxidants thus helping to protect the brain against free radical damage. Finally, magnesium helps to prevent the production of specific chemicals within the body which increase inflammation. In Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, inflammation represents a fundamental mechanism enhancing the formation of brain damaging free radicals.

Folic Acid A large number of studies have confirmed a direct relationship between folic acid status and various neurological problems including dementia, memory loss, and even depression. Like vitamin B12, the importance of folic acid in preserving normal brain function likely stems from its role in reducing homocysteine. Homocysteine is a toxic amino acid, elevation of which is associated with more rapid deterioration in some forms of dementia as well as a dramatic increase in stroke risk.

Pyridoxine Pyridoxine is a B vitamin critical for maintenance of adequate cellular metabolism. Its role in preserving brain function has been demonstrated in several studies showing a direct relationship between low levels of pyridoxine and severity of dementia. Like folic acid and B12, pyridoxine helps reduce homocysteine.

Niacin (as niacinamide) Like pyridoxine, niacin is a B vitamin and a key cofactor in the fundamental process of brain cell energy production. Deficiencies of niacin can profoundly affect brain cell metabolism resulting in dementia.


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