Naturals and Medicines for Parkinson’s Disease (PD)

In this unique, causal-oriented and pictoral guide of PD, I will help you better understand the many, many options for healing to discuss with your health practitioner.

(At the End: See the Testimonial of the individual who completely reversed her Parkinson’s Disease with nutrients and supplements; and

                        See the tissue-targeted treatments employed by a Neurologist.)

Briefly, PD is a slowly progressive neurodegenerative disorder of the production of the neurotransmitter dopamine in cells originating in the Substantia Nigra and releasing their dopamine in the Striatum. The dark areas are dopamine cells in the Striatum, and you can see the marked loss of these cells in PD (on right)


PD Brain Pathways

Our first clue on causes:

PD occurs from the death of dopamine-secreting cells in the Substantia Nigra. Dopamine-secreting cells are among the fastest dying brain cells during aging. Is there a link between the vulnerability of these cells and their involvement in PD? 

Dopamine Cells Dying

In fact there is. These cells are not only prone to free radical damage and death, and dopamine itself easily converted to a free radical, but also these cells are poorly supplied with free radical defenses–So a vicious cycle of free radical damage occurs in PD.

See Appendix IB: Oxidized Dopamine Disrupts Lysosome and Leads to PD

dopamine inflamation

I will first go over all of the potential causes of excessive free radicals (also called “oxidative stress,” or “inflammation.”) And then I will go over the ways you can increase your free radical defenses.

But stay tuned to the end, because I will then present another series of abnormal pathways that could be possible causes, and areas of attack, in your PD plan.

Reference: Wang, X. & Michaelis, E. K. Selective neuronal vulnerability to oxidative stress in the brain. Frontiers in Aging Neuroscience 2, 12 (2010).  

Glutathione List of Effects


Plan 1

Start a trial of intravenous, liposomal, oral or other method of increasing tissue Glutathione. Monitor over the course of several weeks for any lessening of symptoms. The different forms of glutathione can be found here:

See also Dr. Perlmutter, the leading neurologist in the use of glutathione in PD .

Plan 2

Decrease the documented excessive free radicals from Mitochondrial Complex I dysfunction in PD.

Mitochondria in Cell

Complex I is the purple structure below in the Electron Transport Chain (ETC) of the mitochondria–The ETC produces energy. 

(Schapira et al., 1989, 1990)

Complex I

Complex I dysfunction includes dysfunction of CoEnzyme Q10 (CoQ10), NADH and possibly iron (FeS).

Take CoEnzyme Q (CoQ10) in the ubiquinol form, 200 mg/day to improve CoQ10 function.

Try sublingual NADH, 10 mg 1-2 times a day

Measure your iron level, but note that 1) Most PD patients have been found to have excessive iron in their brain tissue; but 2) In PD, you can have a normal serum level and still have excessive amounts in the brain. 

Note that dopamine can auto-oxidize to produce free radicals particularly in the presence of iron and other heavy metals.


Possible causes and consequences of iron overload in Parkinson’s disease. Source: Hindawi

Have a discussion with your health practitioner about reducing iron with slow, on/off cycles of EDTA after reviewing the diagram above showing potential multiple areas of iron-induced damage in PD.  

In fact, recently there was an exciting pre-clinical study presented using a drug that prevented neurologic deterioration by inhibiting iron-mediated aggregation of proteins such as alpha-synuclein.

The drug PBT434 (designed to inhibit oxidative stress and iron-mediated aggregation of Parkinson’s associated proteins like alpha synuclein.) prevented neuronal loss, motor function and cognitive impairment in preclinical models of movement disorders by modulation of intracellular iron.

Presented by Associate Professor David Finkelstein, of the Florey Institute of Neuroscience and Mental Health (Melbourne, Australia).

See Appendix: Iron as a Contributing Factor in PD. 


Plan 3

Decrease the acceleration of free radical formation from “peroxynitrite ion” reported in PD    peroxynitrite ion ONOO-

Ref: Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson’s disease. Ebadi M. Antioxid Redox Signal. 2003 Jun;5(3):319-35

Peroxynitrite Damage

Plan 4

Decrease the inflammatory responses to foods and other substances in the blood. Grossly, this is something you can check with your home blood pressure cuff: 10 minutes after eating, if your blood pressure goes up, you are having an allergy response. Unfortunately, however, this does not detect all allergens, so:

Get a food and environmental allergen test and take antigens, if needed, to limit the inflammatory response.

As you see in the picture below, foods and other substances traveling in the bloodstream (the red circle) have dramatic effects not only on the health of the dopamine cell (“neuron”), but also the supporting “glial,” or “microglial,” cell. 

Plan 5

Take substances which cause the glial cell to secrete its growth factor as above, GDNF–A protector of the dopamine-secreting cell.

Choose from the stimulators listed in Appendix I: “PD: GDNF”

The brain can detect allergies for substances for which we are not aware of any allergy symptoms. When they are exposed, the glial cells become “activated” and secrete signals that bring immune cells (white with purple/blue inside, in picture below) out of the bloodstream and into the tissue next to the glial and dopamine cells.

With glial cell activation, these immune cells secrete damaging “cytokines” that cause even more inflammation and damage to the dopamine-secreting cell.

Inflamed vessel near PD cells

Researchers have noted an increaed presence of pro-inflammatory cytokines in PD brains:

“We and other investigators found increased levels of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6, and decreased levels of neurotrophins such as brain-derived neurotrophic factor (BDNF) in the nigrostriatal region of postmortem brains and/or in the ventricular or lumbar cerebrospinal fluid (CSF) from patients with sporadic PD. These changes in cytokine and neurotrophin levels may be initiated by activated microglia, which may then promote apoptotic cell death of dopamine neurons.”

Plan 6

If you note an allergy, or a deterioration in symptoms after eating: Try to limit the response with:

1. Use of the “elimination diet.”

2. Cytokine inhibitors as needed from the list at

2. NO and/or O- blockers


3. Peroxynitrite Ion blockers  

peroxynitrite ion ONOO-

Plan 6

If you have Candida, treat it aggressively, as the aldehyde isoquinolones from Candida are toxic to PD cells.

Plan 7

Reduce your exposure to pesticides, one of which, Rotenone, is a model for Complex 1 induced free radical damage and cell death. Detoxify your pesticide and other toxin “body burden” with sauna. See Sauna 

Plan 8

Having addressed excessive free radical creation, now increase the inadequate free radical defenses in this brain area: 

Green Tea, Curcumin, Resveratrol, Omega-3 Fatty Acids, Alpha Lipoic Acid, Vitamin C and E, Quercetin, and N-Acetyl-Cysteine (NAC)

Mitochondria ROS Protection Green Tea and Others






Acetyl-L-Carnitine: (The Acetyl form helps brain penetration)

Carnitine Mitochondria


1.5 grams of Carnosine was given daily for 30 days in Parkinson’s patients treated with L-Dopa. The addition of carnosine to the treatment regimen significantly improved neurological symptoms, with a 36 percent improvement in symptoms. Clinical signs of Parkinson’s disease, including decreased bodily movements, and rigidity of extremities, were also significantly improved. ..leading the authors of the study to conclude that carnosine is a reasonable way of improving the treatment of Parkinson’s disease and decreasing the possible toxic effects of standard drug therapy.

Take supplements that put a brake on the self-destructive pathways in the cell in response to excessive oxidative stress.

     a. Rutin and Quercetin and other flavonoids in fruits and vegetables (and available as supplements) reduce PARP-1 cell death signals.

PARP in cell death

      b. Vitamin D: There is a dramatically decreased incidence of a degenerative disease like Parkinson’s (67% lower risk) in people with the highest level of vitamin D.

We now understand that vitamin D stimulates more than 900 genes in human physiology, most of which reside in the brain. These genes code for a variety of activities like reducing inflammation, strengthening nerve cells, and even helping the brain rid itself of viruses.


D. Test for genetic predispositions to oxidative stress:

          a.  Genetic tests can detect genes of detoxification, oxidative stress, and others–Which you can help . One such panel is a Methylation Cycle Panel to see if you have a genetic “SNP” that makes you prone to low glutathione levels or other oxidative stressors. See

          b. Other genes are passed down through the family, and will have to be researched to see the abnormalities that they cause. Approximately 15 percent of people with Parkinson’s Disease have a family history of this disorder. Familial cases of PD  can be caused by mutations in the LRRK2, PARK7, PINK1, PRKN, or SNCA gene, or by alterations in genes that have not been identified.

This completes the section on free radical/inflammation problems and plans, and I will now go over other dysfunctional cellular pathways in PD that I recommend that you speak to your practioner about, as they may be primary causes.  

Lewy Body Edited













The pathological hallmark of Parkinson’s disease is the “clumping” of protein aggregates, especially the protein named “alpha-synuclein,” into “Lewy Bodies” in the cell around the presynaptic terminals.

Alpha-synuclein is found mainly at the tips of nerve cells (neurons) in specialized structures called presynaptic terminals..

The clumping involves abnormal folding of proteins so they do not fit properly, and instead clump together in the cell.

Inside the cell, protein folding occurs in the Endoplasmic Reticulum (the pink structure below), and dysfunction here is called “ER Stress.”

Inside of Cell

ER Stress has been studied extensively for it’s role in PD and its relationship to oxidative stress, mitochondrial dysfunction and proteasomal dysfunction.

ER Stress Free Radicals

So, we will go over ER Stress with alpha-synuclein aggregation, Proteasomal dysfunction, as well as Autophagy and possible ways to improve the dysfunctions.  

Specifically, reduce the misfolding and aggregation of alpha synuclein by reducing ER Stress and improving “Proteasomal Dysfunction” and the “Autophagy Lysosomal Pathway.”

Plan 8

Decrease ER Stress and other causes of alpha-synuclein aggregation with:

Caloric restriction (or intermittent fasting) 

Detoxify the endogenous and environmental toxin “Acrolein.” 

     a. Use Carnosine to detoxify acrolein.

Reduce “Lipid peroxidation.”

      a. Decrease lipid peroxidation with Nrf2 stimulators

Reduce ER Stress by stimulating “Heat Shock Proteins (HSPs)” which act to provide proper protein folding and reduce aggregation by increasing HSPs– especially HSP90, but also HSP70, in PD.

          1. Sauna to heat your core temperature raises HSP production

Although several studies suggest Hsp70 plays a mechanistic role in alpha-synucleinopathies, Hsp90 has been demonstrated to be the dominant HSP involved in regulating alpha-synucleinopathies.

Plan 9

Stimulate the “Autophagy Lysosomal Pathway”–The cell’s garbage disposal system. This research suggests that dysfunction in this pathway could be the primary cause of PD: 

Mov Disord. 2013 Jun;28(6):725-32. Lysosomal impairment in Parkinson’s disease. Dehay Bet al.

Impairment of autophagy-lysosomal pathways (ALPs) is increasingly regarded as a major pathogenic event in neurodegenerative diseases, including Parkinson’s disease (PD).

PD-related glucocerebrosidase GBA deficiency/mutations initiate a positive feedback loop in which reduced lysosomal function leads to α-synuclein accumulation, which, in turn, further decreases lysosomal GBA activity by impairing the trafficking of GBA from the endoplasmic reticulum-Golgi to lysosomes, leading to neurodegeneration. Second, PD-related mutations/deficiency in the ATP13A2 gene lead to a general lysosomal impairment characterized by lysosomal membrane instability, impaired lysosomal acidification, decreased processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished clearance of autophagosomes, collectively contributing to α-synuclein accumulation and cell death. According to these new findings, primary lysosomal defects could potentially account for Lewy body formation and neurodegeneration in PD, laying the groundwork for the prospective development of new neuroprotective/disease-modifying therapeutic strategies aimed at restoring lysosomal levels and function.


Stimulate Lysosomal levels and function to improve the Autophagy Lysosomal Pathway.


Plan 10

Alpha-synuclein can also be turned over by the proteasome (Webb et al. 2003), and proteasome impairments are linked to the formation of inclusions in neurodegenerative disorders, including PD.

Improve the function of the Proteasome to reduce alpha-synuclein aggregation 

          1. Nrf2 stimulators

          2. PARP stimulators, and

          3. Oral antioxidants.

          4. Finally, protect the proteasome by reducing the mitochondria complex I dysfunction.

Complex I dysfunction causes increased free radicals, with Oxidation of Acrolein (direct adduction to 20S Proteasome) and Proteins (binding of aggregated oxidized proteins to the catalytic site of Proteasome 20S) with resulting dysfunction.  (Shamato-Nagai et al 2003)

Recent research of other possible pathways

(Ref: I Celardo, A C Costa, S Lehmann, C Jones, N Wood, N E Mencacci, G R Mallucci, S H Y Loh and L M Martins. Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson’s diseaseCell Death and Disease, June 2016)

suggests that there may be a prior cause that interferes with mitochondrial function and results in the free radical damage: A recent study with a mouse model of PD reported high Endoreticulum Stress (“ER Stress”–Where proteins are folded) as being the first cause, with the tethering of mitochondria (seen below) to the ER as the second cause, thereby preventing them from their mitophagy (or re-cycling), releasing free radicals, with the result that the cell–middle panel–dies.

ER Stress Mitoch Tethered

D. Heavy metals: Reference: 

Toxicology. 1995 Mar 31;97(1-3):3-9. Heavy metals and the etiology of Parkinson’s disease and other movement disorders. Montgomery EB Jr

Heavy metals, such as iron and manganese, are involved in neurologic disease. Most often these diseases are associated with abnormal environmental exposures or abnormal accumulations of heavy metals in the body. There is increasing recognition that heavy metals normally present in the body also may play a role in disease pathogenesis through free radical formation. When a part of the brain known as the basal ganglia is affected, movements become disordered. Parkinson’s disease is one of the most common movement disorders and is related to destruction of neurons in the substantia nigra pars compacta (SNpc) of the basal ganglia. The combination of high concentration of iron and the neurotransmitter, dopamine, may contribute to the selective vulnerability of the SNpc. Dopamine can auto-oxidize to produce free radicals particularly in the presence of iron and other heavy metals.

Many are unaware that heavy metals are absorbed, not only from water and food (fish has been the most publicized), but also through air. It is found on tiny bits of floating particulate matter–one of which is called PD50. Studies have demonstrated the presence of these in the air of big cities, heavily industrialized areas, inside and outside your car in congested traffic, and even in your indoor air.

     1. Get an air filter–At least for your bedroom.

     2. Filter your water.

     3. Choose fish with the least mercury using easily accessible lists on search engines.


Before we go into the treatments for this vicious cycle, I will review the tentative position of dopamine itself in this problem with oxidative stress as dopamine itself can be destroyed by “auto-oxidation.”

Let’s understand the problem with dopamine in PD. In PD, it is the lowering of dopamine levels from damage to, and death of, dopamine cells which is why the first line of treatment from a neurologist is aimed at increasing the dopamine in your brain–either directly with “L-Dopa” (which allows the cells to make more dopamine) and a drug to help L-Dopa to cross into the brain, or indirectly with “Dopamine Agonists” (drugs that stimulate the cell’s production of dopamine in different ways).

In an exciting research trial by a company named Voyager, researchers used gene therapy to increase an enzyme (making dopamine) that normally drops during the deterioration of Parkinson’s Disease. Their trials are in the early phases, however, so it will be years before this could become available.

But as you can imagine, if the oxidation of dopamine is part of the problem, one must use great caution when increasing dopamine levels–It requires a careful balance between “healthy” and “unhealthy” levels of dopamine.

Too much dopamine can worsen oxidative stress both inside the cell and out in the synapse (the area where the cell dumps its dopamine.) In the picture below, I show the life-cycle of dopamine in and out of the “synapse,” or area between the dopamine cell and whatever cell it is communicating to:

A. First, the dopamine is manufactured and extruded into the synapse.

B. The dopamine (orange star-like structure) then moves across the synapse and attaches to a receptor on the next cell–signaling it.

C. The dopamine then disengages from that receptor and moves back across the synapse, and it attaches to a receptor that takes it back into the original cell to break it down.


If there is too much dopamine in this synapse, auto-oxidation can occur, damaging the structures in the synapse. In a different pathway, excess dopamine in the cell can undergo auto-oxidation as well–damaging cellular tissues.

Obviously, this teaches you that you need to communicate to your practitioner the drugs, supplements, or herbs that you are consuming that affect dopamine levels.      

Next, the 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 their function.

   parkinsons disease,

 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

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.


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

Appendix 1: PD: GDNF


Increase with:


  • Calorie Restriction (Ketogenic Diet) R
  • Exercise (like HIST) R R
  • Green Tea R
  • Intermittent Fasting R
  • Plantains R
  • Stress Reduction (GDNF is suppressed by stress) R




  • Apomorphine (see below about downregulation) R
  • Amitriptyline R
  • BT13 R
  • Cabergoline R
  • Clomipramine R
  • Fluoxetine R
  • GDNF Peptide (can be taken intranasally) R R
  • Ibogaine/Noribogaine R R
  • Ladostigil R
  • Leu-Ile R
  • M30 R
  • Mazidol R
  • Mianserin R
  • Nicotine R
  • NSI-189 R
  • Paroxetine R
  • PRE-084 R
  • Pulichalconoid B R
  • Ragasaline R
  • Riluzole R
  • Selegiline (as well as desmethylselegiline) R
  • Telmisartan R
  • Valproic Acid R


  • Electroconvulsive Therapy R
  • Electro Acupuncture R
  • Photobiomodulation R
  • Radiation Therapy R
  • Semen R
  • Transcranial Magnetic Stimulation (as well as chronically/repeated TMS) R

Decrease GDNF

  • Amphetamines (including methamphetamines) R
  • Arsenic R
  • BPA R
  • Caffeic Acid R
  • Chronic morphine or cocaine exposure (increases GDNF then decreases) R
  • Dopamine (as a negative feedback loop) R
  • Dysbiosis R
  • Indole-3-carbinol R
  • Melatonin (conflicting if decreases GDNF, but does increase NGF and BDNFR R
  • Lithium R
  • Spaceflight R
  • Stress R
  • Yohimbine R
  • Zinc R

Appendix 2: Endoplasmic Reticulum Stress: (ER Stress): Could it be a first step in causing PD?

How to reduce ER Stress 

This includes reducing activation of the

1. JNK pathway

2. NFkB, and

3. Cytokine production.

And reducing 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.”

ER Stress study in mice suggests it is the first cause of PD Appendix: Iron as a cause of PD:

The neurodegeneration that occurs in Parkinson’s disease is a result of stress on the endoplasmic reticulum in the cell rather than failure of the mitochondria as previously thought, according to a study in fruit flies. It was found that the death of neurons associated with the disease was prevented when chemicals that block the effects of endoplasmic reticulum stress were used.

Some inherited forms of early-onset Parkinson’s disease have typically been blamed on poorly functioning mitochondria, the powerhouses of cells. Without reliable sources of energy, neurons wither and die. This may not be the complete picture of what is happening within cells affected by Parkinson’s. Researchers from the MRC Toxicology Unit at the University of Leicester used a common fruit fly to investigate this further; fruit flies were used because they provide a good genetic model for humans.

Studies on human subjects are of limited use for elucidating the signaling pathways and cellular processes underlying the neurodegenerative process. This is because both ethical and technical constraints limit the extent to which genetic analysis can be performed in humans.

Flies are a well-established model animal to understand the molecular mechanisms of human diseases. This is because about 75% of human disease-causing genes are found in the fly in a similar form. Also, they are easy to work with, breed quickly and many tools are available to manipulate any genes in the fly. In flies, potential therapeutic drugs can be mixed with food and readily tested.

It was found that the bulk of the damage to neurons with damaged mitochondria stems from a related but different source — the neighbouring maze-like endoplasmic reticulum (ER).

The ER has the important job of folding proteins so that they can do the vast majority of work within cells. Misfolded proteins are recognized by the cell as being dangerous. Cells halt protein production if there are too many of these harmful proteins present. While this system is protective, it also stalls the manufacture of vital proteins, and this eventually results in the death of neurons.

To find out if ER stress might be at play in Parkinson’s, a team led by Dr Miguel Martins analyzed fruit flies with mutant forms of the pink1 or parkin genes. Mutant forms of pink1 and parkin are already known to starve neurons from energy by preventing the disposal of defective mitochondria. These genes are also mutated in humans and result in hereditary versions of the disease. Much like Parkinson’s patients, flies with either mutation move more slowly and have weakened muscles. The insects struggle to fly and they lose dopaminergic neurons in their brains — a classic feature of Parkinson’s.

Compared to normal flies, Miguel’s team found that the mutants experienced large amounts of ER stress. The mutant flies did not manufacture proteins as quickly as the non-mutants. They also had elevated levels of the protein-folding molecule BiP, a telltale sign of stress.

One function of pink1 and parkin genes is to help degrade mitofusin — a protein that tethers the endoplasmic reticulum to mitochondria. Mutant flies have an abundance of this protein. It was found that the mutants had more of their mitochondria attached to the ER than normal flies. For this reason, the researchers suggest that ER stress is related to extra tethering of mitochondria, thereby preventing the removal of defective versions of the organelle.

Mutant flies, which have more of these tethers, have fewer dopaminergic neurons, which can have an adverse effect on the brain. By reducing the number of these tethers it is possible to prevent the loss of the neurons. When the researchers experimentally lowered the amount of mitofusin in the mutants, the number of tethers fell and the neuron number increased again. The flies’ muscles also remained healthy despite the mitochondria themselves still being defective.

These results suggest that the neurodegeneration seen in Parkinson’s is a result of ER stress rather than a general failure of the mitochondria. The scientists were able to prevent neurodegeneration in mutant flies not only by reducing mitofusin, but also with chemicals that block the effects of ER stress.

Dr Miguel Martins said: “This research challenges the current held belief the Parkinson’s disease is a result of malfunctioning mitochondria. By identifying and preventing ER stress in a model of the disease it was possible for us to prevent neurodegeneration. Lab experiments, like this, allow us to see what effect ER stress has on Parkinson’s disease. While the finding so far only applies to fruit flies, we believe further research could find that a similar intervention in people might help treat certain forms of Parkinson’s.”

Story Source:

Materials provided by University of LeicesterNote: Content may be edited for style and length.

Journal Reference:

  1. I Celardo, A C Costa, S Lehmann, C Jones, N Wood, N E Mencacci, G R Mallucci, S H Y Loh and L M Martins. Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson’s diseaseCell Death and Disease, June 2016 DOI: 10.1038/cddis.2016.173


Appendix 3: Iron as a Contributing Factor in PD.

High levels of iron can cause the oxidation of dopamine, which results in the production of hydrogen peroxide (H2O– a reactive oxygen species – the stuff that is used to bleach hair and is also used as a propellant in rocketry!). This reaction can cause further oxidative stress that can then lead to a range of consequences including protein misfolding, lipid peroxidation (which can cause the accumulation of the Parkinson’s associated protein alpha synuclein), mitochondrial dysfunction, and activation of immune cells in the brain.

Chelating Iron

Iron is a chemical element (symbol Fe). It has the atomic number 26 and by mass it is the most common element on Earth (it makes up much of Earth’s outer and inner core). It is absolutely essential for cellular life on this planet as it is involved with the interactions between proteins and enzymes, critical in the transport of oxygen, and required for the regulation of cell growth and differentiation.

So why then – as Rosalind asked in Shakespeare’s As You Like It – “can one desire too much of a good thing?”

Well, if you think back to high school chemistry class you may recall that there are these things called electrons. And if you have a really good memory, you will recall that the chemical hydrogen has one electron, while iron has 26 (hence the atomic number 26).


The electrons of iron and hydrogen. Source: Hypertonicblog

Iron has a really interesting property: it has the ability to either donate or take electrons. And this ability to mediate electron transfer is one of the reasons why iron is so important in the body.

Iron’s ability to donate and accept electrons means that when there is a lot of iron present it can inadvertently cause the production of free radicals. We have previously discussed free radicals (Click here for that post), but basically a free radical is an unstable molecule – unstable because they are missing electrons.


How free radicals and antioxidants work. Source: h2miraclewater

In an unstable format, free radicals bounce all over the place, reacting quickly with other molecules, trying to capture the much needed electron to re-gain stability. Free radicals will literally attack the nearest stable molecule, to steal an electron. This leads to the “attacked” molecule becoming a free radical itself, and thus a chain reaction is started. Inside a living cell this can cause terrible damage, ultimately killing the cell.

Antioxidants can help try and restore the balance, but in the case of iron overload iron doctors will prescribe chelator treatment to deal with the situation more efficiently. By soaking up excess iron, we can limit the amount of damage caused by the surplus of iron.

So what research has been done regarding iron content and the Parkinsonian brain?

Actually, quite a lot.

In 1968, Dr Kenneth Earle used an X-ray based technique to examine the amount of iron in the substantia nigra of people with Parkinson’s disease (Source). The substantial nigra is one of the regions in the brain most badly damaged by the condition – it is where most of the brain’s dopamine neurones resided.


The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp

Earle examined 11 samples and compared them to unknown number of control samples and his results were a little startling:

The concentration of iron in Parkinsonian samples was two times higher than that of the control samples.

Since that first study, approximately 30 investigations have been made into levels of iron in the Parkinsonian brain. Eleven of those studies have replicated the Earle study by looking at postmortem tissue. They have used different techniques and the results have varied somewhat:

  • Sofic et al. (1988)                             1.8x increase in iron levels
  • Dexter et al. (1989)                         1.3x increase in iron levels
  • Uitti et al. (1989)                              1.1x increase in iron levels
  • Riederer et al 1989                         1.3x increase in iron levels
  • Griffiths and Crossman (1993)     2.0x increase in iron levels
  • Mann et al. (1994)                           1.6x increase in iron levels
  • Loeffler et al. (1995                      0.9   (lower)
  • Galazka-Friedman et al., 1996     1.0   (no difference)
  • Wypijewska et al. (2010)               1.0   (no difference)
  • Visanji et al, 2013                            1.7x increase in iron levels

Overall, however, there does appear to be a trend in the direction of higher levels of iron in the Parkinsonian brains. A recent meta-analysis of all this data confirmed this assessment as well as noting an increase in the caudate putamen (the region of the brain where the dopamine neuron branches release their dopamine – Click here for that study).

Brain imaging of iron (using transcranial sonography and magnetic resonance imaging (MRI)) has also demonstrated a strong correlation between iron levels in the substantia nigra region and Parkinson’s disease severity/duration (Click hereand here to read more on this).

Thus, there appears to be an increase of iron in the regions most affected by Parkinson’s disease and this finding has lead researchers to ask whether reducing this increase in iron may help in the treatment of Parkinson’s disease.

How could iron overload be bad in Parkinson’s disease?

Well in addition to causing the production of free radicals, there are many possible ways in which iron accumulation could be aggravating cell loss in Parkinson’s disease.


Possible causes and consequences of iron overload in Parkinson’s disease. Source: Hindawi

High levels of iron can cause the oxidation of dopamine, which results in the production of hydrogen peroxide (H2O– a reactive oxygen species – the stuff that is used to bleach hair and is also used as a propellant in rocketry!). This reaction can cause further oxidative stress that can then lead to a range of consequences including protein misfolding, lipid peroxidation (which can cause the accumulation of the Parkinson’s associated protein alpha synuclein), mitochondrial dysfunction, and activation of immune cells in the brain.

And this is just a taster of the consequences.

Appendix 4: Medications for PD

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.


Appendix 5: 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.


Appendix V: Oxidized Dopamine Disrupts Lysosome and Research Suggesting it as a Cause of  PD (Specifically, decreased lysosomal glucocerebrosidase activity)


Title: Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease
Authors: Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D
Journal: Science, 07 Sept 2017 –
PMID: 28882997

The researchers who conducted this study began by growing dopamine neurons – a type of cell badly affected by Parkinson’s disease – from induced pluripotent stem (IPS) cells.

What are induced pluripotent stem cells?

This is Prof Shinya Yamanaka:


Prof Yamanaka is the director of Center for induced Pluripotent Stem Cell Research and Application (CiRA); and a professor at the Institute for Frontier Medical Sciences at Kyoto University.

In 2006, his research group published a report demonstrating how someone can take a skin cell and re-program it so that it becomes a stem cell – a cell capable of becoming any kind of cell in the body.

Here’s that study:


Title: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
Authors: Takahashi K, Yamanaka S.
Journal: Cell. 2006 Aug 25;126(4):663-76.
PMID: 16904174                (This article is OPEN ACCESS if you would like to read it)

Shinya Yamanaka‘s team started with the hypothesis that a gene – the section of DNA that provides the instructions for making a particular protein – which is important to the maintenance of embryonic stem cells (the cells that give rise to all cells in the body) might also be able to cause an embryonic-like state in mature adult cells. They selected twenty-four genes that had been previously identified as important in embryonic stem cells to test this idea. They used re-engineered retroviruses to deliver these genes to mouse skin cells. The retroviruses were emptied of all their disease causing properties, and could thus function as very efficient biological delivery systems.

The skin cells were engineered so that only cells in which reactivation of the embryonic stem cells-associated gene, Fbx15, would survive the testing process. If Fbx15 was not turned on in the cells, they would die. When the researchers infected the cells with all twenty-four embryonic stem cells genes, remarkably some of the cells survived and began to divide like stem cells.

In order to identify the genes necessary for the reprogramming, the researchers began removing one gene at a time from the pool of twenty-four. Through this process, they were able to narrow down the most effective genes to just four: Oct4, Sox2, cMyc, and Klf4, which became known as the Yamanaka factors.

This new type of cell is called an induced pluripotent stem (IPS) cell – ‘pluripotent’ meaning capable of any fate.

Making IPS cells. Source: learn.genetics

Induced pluripotent stem cell are stem cells – ‘pluripotent’ meaning capable of any fate – that have been derived from an adult, mature cell (usually skin cells). The adult cell has been ‘induced’ into being a stem cell, by the reprogramming process. The discovery of these cells means that patient-specific tissue can be generated in petri dishes (or cell culture) and investigated experimentally – the underpinnings of personalised medicine.

Ok, so the researchers used these IPS cells to make dopamine neurons?


They took skins cells from people with different types of Parkinson’s disease (based on different genetic mutations associated with the condition) and with a little bit of biological magic they made IPS cells, which were then grown into dopamine neurons. These cells from different types of Parkinson’s disease included skin cells from people with genetic mutations in the DJ-1 gene (Click here to learn more about DJ-1), the Parkin gene, the PINK1 gene (Click here and here to learn more about Parkin and PINK1), and the LRRK2 gene (Click here to learn more about LRRK2).

The researchers started with the cells that have DJ-1 mutations. After 50 days of growing these cells, the investigators noticed that the cells had very high levels of oxidative stress. DJ-1 is present in almost all cells, including those of the brain. And it is a busy protein, involved in many different roles required for normal biological activity. One of the primary functions of DJ-1, however, is to help protect cells from oxidative stress, so it is no real surprise that there is an increase in levels of oxidative stress.


Ok, got it. The DJ-1 cells had high levels of oxidative stress. Did the researchers notice anything else?

Yes, the DJ-1 cells also exhibited the accumulation dense clustering of neuromelanin. And before you asks: Neuromelanin is the brain version of a protein called melanin, which is a pigment found in the skin, eyes, and hair. In the brain, certain types of cells, such as the dopamine neurons, produce neuromelanin.


Neuromelanin (brown) in dopamine neurons. Source: Schatz

Neuromelanin is produced from the oxidation of dopamine. Thus, a gradual build up of neuromelanin in the DJ-1 dopamine neurons indicates an increase in the levels of oxidised dopamine.

And this is exactly what the researchers found: increased levels of oxidised dopamine. And the levels of oxidised dopamine progressively increased in the DJ-1 dopamine neurons from day 70 in cell culture to day 150. But here’s the interesting thing: The same increase in oxidised dopamine was not observed in dopamine neurons made from IPS cells from healthy control subjects. This effect was specific to the DJ-1 cells.

That was until the researchers looked at dopamine neurons made from IPS cells collected from people with ‘idiopathic’ Parkinson’s disease (idiopathic meaning that no genetic mutation is involved). These dopamine neurons ALSO exhibited increased levels in oxidised dopamine levels, but only at later time points (between day 150 and day 180 in cell culture).

Now, neuromelanin is often found in structures called lysosomes. Lysosomes are small bags of digestive enzymes that can be found inside cells. They help to break down proteins like neuromelanin that have served their function and need to be digested and disposed of (or recycled).


How lysosomes work. Source: Prezi

Inside the lysosomes are enzymes (such as glucocerebrosidase) which help to break material down into useful or disposable parts. The lysosome will fuse with other small bags (called vacuole) which act as storage vessels of food or waste inside a cell. The enzymes from the lysosome will mix with the material in the vacuole and digest it (or it break down into more manageable components).

Given the increase in neuromelanin levels in the DJ-1 dopamine neurons, the researchers wondered if the lysosomal recycling function was impaired in these cells, but further analysis suggested no detectable impairment.

What they did find, however, was a decrease in the activity of the lysosomal enzyme glucocerebrosidase at day 70.

This decrease was specific to glucocerebrosidase – there was no drop in the activity of other lysosomal enzymes – and the dopamine neurons from IPS cells from idiopathic Parkinson’s disease also exhibited a delayed decrease in glucocerebrosidase activity (starting at day 180 in cell culture).

Why is gluco-cere-bro-si-dase important?

Genetic mutations in the gene that provides the instructions for the production of this enzyme (the gene is called GBA) are the most common genetic variation that are associated with increased risk of developing Parkinson’s disease.

And this is where the story starts to get interesting:

When the researchers next looked at dopamine neurons made from IPS cells from people with other Parkinson’s associated genetic mutation (such as Parkin, PINK1, and LRRK2 – all mentioned above), they found a similar increase in oxidised dopamine across all of the cells, as well as decreased glucocerebrosidase activity – particularly in Parkin mutant dopamine neurons.

These results suggested that to the researchers that oxidative stress directly modifies and disrupts glucocerebrosidase enzymatic activity.

Wow. So could the researcher treat the cells with anything to correct this?

Yes indeed, and that is exactly what they did next. They tested several different treatments.

First, they treated the cells with Acetylcysteine (also known as N-acetylcysteine or simply NAC). I have discussed NAC in a previous post (Click here to read that post).

Acetylcysteine-2D-skeletalAcetylcysteine. Source: Wikimedia

NAC (commercially named Mucomyst) is a prodrug – that is a compound that undergoes a transformation when ingested by the body and then begins exhibiting pharmacological effects. Acetylcysteine serves as a prodrug to a protein called L-cysteine, and – just as L-dopa is an intermediate in the production of dopamine – L-cysteine is an intermediate in the production of another protein called glutathione.

Glutathione-from-xtal-3D-ballsGlutathione (pronounced “gloota-thigh-own”) is a potent antioxidant. It is produced naturally in nearly all cells. In the brain, glutathione is concentrated in the helper cells (called astrocytes) and also in the branches of neurons, but not in the actual cell body of the neuron.

When the researcher treated the DJ-1 mutant cells with NAC, it stopped the accumulation of oxidised dopamine and improved lysosomal glucocerebrosidase activity. The Parkinson’s disease-associated protein alpha synuclein was also found to have elevated levels in the DJ-1 mutant cells and NAC treatment also found to have a beneficial effect on reducing levels of this protein.

Next, the researchers treated the cells with a calcium channel antagonist called ‘Isradipine’. I have been meaning to write a post about this drug for a while because there is a big clinical trial ongoing for Isradipine in Parkinson’s disease – it is called STEADY-PD III (Click here to learn more about it).

Isradipine (tradenames DynaCirc, Prescal) is a calcium channel blocker, which is a class of drugs usually prescribed for the treatment of high blood pressure (and thus reducing the risk of stroke or heart attack). Calcium channels are found in the membrane of excitable cells (such as muscle, glial cells, neurons, etc.).

The concentration of calcium outside the cell is normally several thousand times higher than inside the cell. Activation of calcium channels allows calcium to rush into the cell and makes the cell excited. Prof Frank Church over at the ‘Journey with Parkinson’s’ blog has a great page on Isradipine (Click here to read that post).

Calcium getting cells excited. Source: STEADY-PD III

Increased calcium channel activation is also known to enhance oxidant stress and dopamine synthesis. When the researchers tested Isradipine on the dopamine neurons in cell culture, they found that it significantly decreased the accumulation of oxidised dopamine.

Thus, the researchers were able to interupt the toxic cascade that was affecting these dopamine neurons… in cell culture at least.

Does the effect work in mouse models of these genetic forms of Parkinson’s disease?

Ok, so this is where this research report is extremely interesting.

The investigators next examined whether the toxic cascade of events that they observed in the human dopamine neurons grown in cell culture also occurs in mouse models of Parkinson’s disease. They started by looking at the dopamine neurons in mice lacking the DJ-1, and they found….



There was no increase in the amounts of oxidised dopamine (at both 3 months or 12 months of age). There was also no increase in the amount of alpha synuclein in these mice. AND levels of glucocerebrosidase activity were normal.

Strange, huh?

The researchers were left scratching their heads for a moment. But then they decided to model Parkinson’s disease in these mice in a more disease-relevant way. They figured that since mutations in the alpha synuclein gene results in the accumulation of alpha synuclein protein in a genetic form of Parkinson’s disease, they would increase levels of mutant alpha synuclein protein in the DJ-1 mutant mice and see what impact this has on oxidised dopamine levels.

And guess what happened?

Suddenly the DJ-1 mutant mice (that had an over production of alpha synuclein) had elevated levels of oxidised dopamine and decreased lysosomal glucocerebrosidase activity!

Is it just increased levels of alpha synuclein that can cause these problems?


The researchers also investigated whether simply increasing dopamine levels might also trigger problems in the DJ-1 mutant mice. They started feeding the mice with Levodopa-supplemented food to the mice, and………..this led to oxidised dopamine accumulation in the dopamine neurons as well. Levodopa treatment of the DJ-1 mutant mice (but not normal mice) also disrupted glucocerebrosidase enzymatic activity, increased alpha synuclein levels, AND caused the loss of dopaminergic neurons. Plus, the investigators repeated this experiment in cell culture with dopamine neurons from DJ-1 mutant mice and they found the same results.

Oh boy, so Levodopa can cause an increase in oxidised dopamine?

According to the results of this study report, yes.

And human dopamine neurons demonstrated higher levels of dopamine when compared to their mouse equivalent, suggesting a difference in dopamine production between the two species. Supporting this idea, the researchers found that Levodopa treatment was sufficient to increase oxidised dopamine in dopamine neurons made from IPS cells from healthy control humans, but this was not possible in dopamine neurons made from IPS cells from normal mice.

Thus (again, according to the results of this study) Levodopa treatment in humans appears to increase levels of oxidised dopamine.

Oh’ll man, this is bad! L-dopa increases the level of oxidised dopamine! I should stop my L-dopa treatment to lower my levels of oxidised dopamine!

No, you shouldn’t.

By the time someone is diagnosed with Parkinson’s disease, 50% of the dopamine neurons in the substantia nigra have been lost. When Levodopa treatment is initiated, the remaining dopamine neurons may take up some of the medication, but in a lot of cases other cells in the brain will also take up the Levodopa and produce dopamine. The enzyme that converts Levodopa into dopamine is called aromatic amino-acid decarboxylase (or AADC). This enzyme is not specific to dopamine neurons, it is found in many different cells including glia cells and serotonin neurons. Most of these cells are better able to handle oxidative stress than the dopamine neurons.

Serotonin (5HT) neuron producing dopamine from L-dopa. Source: galoncockwould

If you are concerned about these findings, however, please discuss them with your physician before making any changes to your treatment regime. Alternative treatments that do not cause excess levels of oxidative dopamine (such as dopamine agonists) are available. But I would like to add that this study needs to be independently replicated before we can consider the results validated. And clinical studies of dopamine agonists have demonstrated limited disease modifying potential of the drugs on Parkinson’s disease (Click here to read more about this), so it is unlikely that this oxidised dopamine idea is the cause of disease progression in Parkinson’s.

So what does it all mean?

From “To a Mouse,” by Robert Burns comes the line “The best laid schemes o’mice an’ men/Gang aft agley”, which was used in the title of John Steinbeck’s classic ‘Of mice and men’. It seemed appropriate here because this new research suggests that our efforts to use lower species to help explain our ailments ‘gang aft agley’.


Having said that, if the researchers behind the report we reviewed today had not alternated between mice and human cells, they would not have observed the differences that they found.

The research report we have reviewed today raises concerns about comparing experimental results observed in mice with disease-associated phenomenon in humans. The investigators found that a toxic cascade of oxidised dopamine build up and reduction of enzymatic recycling of the dopamine causes problems in human cells, but not mouse cells – unless those cells are over supplied with Levodopa.

Whether oxidised dopamine is playing a role in the dysfunction and death of dopamine neurons in Parkinson’s disease, is yet to be determined. While the results of this new study are very interesting and point towards the beneficial use of antioxidants and calcium channel blockers, we need independent replication of the results to confirm the findings. It would also be interesting to conducted an analysis of clinical notes comparing outcomes between people treated with Levodopa and dopamine agonists to assess whether any ‘oxidised dopamine’ effect could be speculated upon in the clinic

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