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Antioxidants and Parkinsons

The cause of Parkinsons disease is not known at present, and there are many theories as to why the loss of nerve cells that characterises the condition occurs. In recent years, there has been some interest in the role of free-radical damage, particularly the damage caused by highly reactive molecules, in Parkinsons and other conditions. Antioxidant chemicals have also come under scrutiny as a possible future therapy for Parkinsons, because of their ability to prevent the damage caused by free radicals. Many of these are available either separately or in multivitamin supplements, and a number of claims have been made for the effectiveness of a number of different antioxidants. The Parkinsons Disease Society (PDS) receives a lot of enquiries about antioxidants and dietary supplements, often based on reports found in the media, on the internet, or from particular organisations. Claims for the effectiveness of certain products are often theoretical, however, and do not always have sufficient evidence from scientific research to support them. This information sheet aims to outline the role of antioxidants in the body and brain, and their potential value in Parkinsons. It also identifies some of the antioxidant chemicals that are often discussed in relation to Parkinsons. Where research has been carried out on these chemicals, it is discussed. In the absence of any concrete evidence from reputable sources, the PDS is unable to recommend specific brands or dosages. If you are thinking about taking any supplement, you should discuss this with your GP or Parkinsons specialist. What are antioxidants? Antioxidants are chemicals produced by the body or absorbed from the diet to neutralise the effects of free radicals. Free radicals are highly reactive and potentially very damaging molecules, which can be produced by normal chemical reactions in the body or absorbed from outside sources (such as cigarette smoke, pollutants, or prolonged exposure to sunlight). Free radicals only last for very short periods of time, but have the potential to do damage to the bodys cells during that time. Technically, free radicals are molecules that have an odd number of particles known as electrons, either one too many or one too few. This causes the molecules to become unstable and highly reactive, and in an attempt to address the electron imbalance, freeradicals react with neighbouring molecules. This process, known as oxidation, is thought to cause damage known as oxidative stress to tissues, cells and neurons. Dopamine-producing cells in a region of the brain known as the substantia nigra appear to be particularly at risk from free-radical generation and damage. It is these cells that are lost in Parkinsons. There is also some evidence that oxidative stress may cause or contribute to the condition: for example, people with Parkinsons have been found to have increased levels of iron in the brain, especially in the substantia nigra. Iron is a powerful agent of free-radical damage: It can potently stimulate oxidative stress if it is in free or reactive form. Normally, a cell will surround the iron with a protein called ferritin (a process known as chelation), which prevents

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it from stimulating oxidative stress, but levels of ferritin are also found to be decreased in the brains of people with Parkinsons. Antioxidants (also known as free-radical scavengers) keep cell damage under control by offering themselves as easy targets for the actions of free radicals. Antioxidants trap (de-energise or stabilise) lone free-radical molecules and make them stable enough to be transported to an enzyme, which combines two stabilised free radicals together to neutralise both. The brain contains multiple antioxidant defences. However, the level of one of the major antioxidants, glutathione, is reduced in the brains of people with Parkinsons (described below). How are antioxidants used in the treatment of Parkinsons? At the moment, there is no drug treatment for Parkinsons that deliberately seeks to combat oxidative stress through the action of antioxidants. The drug selegiline (trade names Eldepryl or Zelapar) received attention some time ago, as it was thought that it might protect the cells of the brain from the damage caused by oxidative stress. Selegilines main action is to slow the breakdown of dopamine in the brain by inhibiting the action of an enzyme known as monoamine oxidase (MAO). A large, five-year study known as the DATATOP (Deprenyl and Tocopherol Antioxidative Therapy for Parkinsons Disease) study1 investigated whether treatment with selegiline would also slow the progression of Parkinsons by protecting dopamine-producing cells from the damage caused by oxidative stress. Although
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it did seem to delay the need for levodopa treatment, this benefit was only observed in the short term. Selegiline is widely used by people with Parkinsons, but any claims for its neuroprotective benefit (i.e. protecting the cells from damage) remain unproven. More information on selegiline is available in the booklet the Drug Treatment of Parkinsons Disease. Recently, another MAO inhibitor has been developed, called rasagiline, that not only inhibits the breakdown of dopamine but has also been shown in nerve cells cultured in the laboratory to inhibit apoptosis, a mechanism by which neurons die. Selegiline also had neuroprotective effects by inhibiting apoptosis in neuronal cultures exposed to toxins, but when the drug was administered to humans, the body produced derivative of the drug that failed to keep their neuroprotective effects. It is hoped that rasagiline will not undergo the same metabolic fate as selegiline when administered to humans and that it will not only inhibit dopamine breakdown but also may protect the remaining dopaminergic neurons in Parkinsons. However, this has yet to be tested. Have any antioxidants been shown to help Parkinsons? A number of antioxidant compounds have received specific attention from researchers interested in Parkinsons and some of these have been tested. Of those that have been studied, several have shown some promise as protective agents, and these will be discussed in this section. Coenzyme Q10 Coenzyme Q10 (or CoQ10) is a substance present in every cell of the body. It is also

The Parkinsons Study Group (1993) Effects of Tocopherol and Deprenyl on the Progression of Disability in Parkinsons Disease New England Journal of Medicine; 328: 176183

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naturally present in small amounts in a wide variety of foods but is particularly high in organ meats (such as heart, liver and kidney) as well as in beef, soya oil, sardines, mackerel and peanuts. It is also available in supplement form. The levels of CoQ10 in food are relatively low compared with the amounts available in supplement form. A study carried out by researchers in 2002 in the USA with 80 people with Parkinsons has suggested (but not proven) that high doses of CoQ10, as large as 1200mg daily, can slow the progression of Parkinsons.2 Progression was measured according to the participants function, i.e. with what degree of difficulty they carried out tasks. The actual effect of CoQ10 on the affected cells in the brain could not be ascertained, but according to the measures made by the researchers, high dosages could slow the progression of disability by up to 44%. The researchers involved in this study have warned that they would not be able to recommend CoQ10 as a treatment for Parkinsons based on these results alone. A group of 80 people is not large enough for any definite conclusions to be drawn on the effects of this supplement. The participants had been diagnosed with Parkinsons within five years of beginning the trial and had received no drug treatment for their symptoms up to that point. The researchers were concerned that they should not attribute a symptomatic benefit to CoQ10 when it might in fact be coming from another drug or treatment.

The researchers also warn that their claims for a slowing in the rate of progression are based on their observations of the function of participants. They have not been able to investigate whether the people receiving CoQ10 actually had less damage to the cells affected. However, the results of this small study are encouraging, and the researchers feel that there is enough evidence to continue the research, to broaden their understanding of the effects of CoQ10 on Parkinsons. They are currently carrying out a further study, involving a much larger number of participants over a longer period of time, in order to assess the true effects of the compound. They also want to assess the effects of even larger doses of CoQ10, up to 3000mg daily. With evidence from a larger study, they hope to be better able to draw some conclusions. For more information, see the information sheet Coenzyme Q10. Polyphenols A number of other antioxidant substances are widely found in nature, and some have been investigated as neuroprotective agents in Parkinsons. Green tea A report has suggested that green tea, which is rich in agents termed polyphenols, protected dopamine-producing cells from damage in a mouse model of Parkinsons.3 This study has not been replicated in humans, and it is difficult to tell whether green tea would have the same effect for people with Parkinsons,
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Shults CW et al (2002) Effects of Coenzyme Q10 in Early Parkinson Disease: Evidence of Slowing of the Functional Decline Archives of Neurology; 59:10

Levites Y et al (2001) Green tea polyphenol (-)-epigallocatechin-3-gallate prevents N-methyl-4phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. Journal of Neurochemistry; 75(5) 107382

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or whether very large amounts would have to be consumed to reproduce the effect. Overconsumption of green tea could result in stomach upsets, and could also interfere with the normal absorption of iron by the body.The use of green tea should be discussed with a doctor or health professional. Tangeretin Tangeretin is a polyphenol that is found in tangerines. Research has shown that, unlike other compounds, tangeretins molecular structure is small enough to easily cross the blood-brain barrier, the mechanism that controls the passage of substances from the blood to the brain and spinal cord. Researchers involved in the study of tangeretin have demonstrated that, in a rat model of Parkinsons, the compound does help to protect cells from damage due to oxidative stress.4 However, further study needs to be carried out to assess whether a similar effect can be found in humans. As with the green tea study, very large amounts of tangerine would have to be consumed to reproduce the dose used here, and this is not recommended. Folic acid (folate) Research has suggested that a deficiency of folic acid (folate) in the diet could make the brain more susceptible to oxidative stress, and therefore conditions such as Parkinsons in which oxidative stress may be involved.
Datla KP et al (2001) Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinsons disease Neuroreport; 12(17): 387138755 5 Duan W et al (2002) Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinsons disease Journal of Neurochemistry; 80(1): 101110
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A recent study showed that mice fed a diet low in folic acid had increased levels of homocysteine, a chemical found in the blood-stream that is thought to contribute to the process of cell death.5 Folic acid usually converts homocysteine into a harmless chemical which is then excreted from the body, but reduced folate is obviously less well able to perform this task. The authors of the mouse study have suggested that a diet with sufficient folic acid may help protect against free-radical damage. It is available in supplement form, but is also found in vegetables, seeds, etc and is already added to many processed, fortified foods. Good sources of folate are orange juice, dried beans, green peas, asparagus, beets, Brussels sprouts, broccoli, corn, spinach and other dark green leafy vegetables, nuts and seeds. There is no evidence, so far, to suggest that the results from the mouse study can be replicated in humans, and while folic acid is essential to a healthy diet, it is important not to consume more than the recommended levels. Your doctor, dietician or another health professional should be able to advise you on whether extra folic acid is needed in your diet. What other antioxidants have been discussed/are being researched? The role of antioxidants in Parkinsons is receiving increasing attention, within both the scientific and lay communities. As well as the compounds discussed above, it is thought that many other chemicals may have some effect on the progression of the condition. However, these have not yet been studied properly, or if they have, the benefits have not been as

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striking as had been hoped. Some of the more commonly discussed substances that would come under this heading are detailed below. Glutathione Glutathione is an important antioxidant chemical found in the brain and throughout the body. As well as guarding against freeradical damage, it has the added effect of enhancing the function of other antioxidants. Glutathione has been found in reduced quantities in the substantia nigra of people with Parkinsons, which has led some to suspect that it plays a prominent role in the death of dopamine-producing cells. Interest in glutathione as a therapy for Parkinsons has been hampered by the difficulty in administering it. Taken orally, it can be easily broken down by the liver and digestive system, and its molecular structure does not allow it to cross the blood-brain barrier freely. One published study has reported significant improvement in symptoms for people with Parkinsons when administered glutathione intravenously (through a drip into the bloodstream), twice a day for one month.6 It was also argued that glutathiones antioxidant effects might slow the progression of Parkinsons. However, this study was very small with only nine people taking part, was conducted over a relatively short 30day period and its findings have not been reproduced on a larger scale. Although symptomatic benefit was observed in the participants, any argument that the treatment slowed the progression of the Parkinsons was largely assumed, and not examined rigorously.

As it has proved difficult to find a readily absorbed source of glutathione, there is some interest in the chemical N-acetyl-L-cysteine, which is believed to increase the bodys own production of glutathione. Although supplements of this antioxidant are available, it should be noted that there has been no actual research into its effects on Parkinsons symptoms or progression. Vitamin E Vitamin E also has antioxidant properties, and early studies suggested that it may have neuroprotective effects, i.e. that it might protect the dopamine-producing cells from damage. Vitamin E is found in nuts and seeds, avocados, mayonnaise, wheatgerm, peanut butter, dark green leafy vegetables, and asparagus. The DATATOP study, which investigated the drug selegiline (Eldepryl), also investigated the neuroprotective potential of vitamin E, but found that claims for a significant benefit from vitamin E were unfounded and that it had very little specific effect on the progress of Parkinsons. These findings have been confirmed by a number of more recent trials.7 A recent study has suggested that a high intake of vitamin E-rich foods in the diet, but not in supplements, may be associated with a reduced risk of Parkinsons. However, the researchers involved in the study were reluctant to argue that vitamin E directly protects dopamine reproducing cells,
Sechi D et al (1996) Reduced intravenous glutathione in the treatment of early Parkinsons disease Progress in neuropsychopharmacology & biological psychiatry; 20(7): 11591170 7 Zhang SM et al (2002) Intakes of vitamins E and C, carotenoids, vitamin supplements, and PD risk Neurology; 59(8): 116111699
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suggesting instead that foods rich in vitamin E may contain other, unidentified agents that are responsible for the protection observed. Alternatively, they suggest, moderate amounts of vitamin E may reduce the risk of Parkinsons, but this benefit is lost with the higher intake seen in supplements. The clinical benefit of vitamin E remains a controversial topic, and has not been resolved conclusively. In the absence of definitive evidence, it is not usually recommended as a specific treatment for Parkinsons. It is also important to note that high levels of vitamin E might actually be toxic. SAMe Studies in animals have shown that the antioxidant molecule S-adenosylmethionine (SAMe, pronounced sammy) reduces oxidative stress in the brains of rats. As with glutathione, lower levels of SAMe have been found in people with Parkinsons. Recent media reports have suggested that supplementing your diet with large amounts of SAMe can enhance the effectiveness of levodopa medication, and reduce the risk of side effects from the medication.

Parkinsons symptoms, or the effectiveness of levodopa, in any way. Indeed, it has been suggested that the effect of levodopa on SAMe levels may actually help cause tolerance of the drug. SAMe has also been promoted as an antidepressant. A small pilot study was carried out to see if SAMe supplements would benefit symptoms of depression in people with Parkinsons symptoms.9 The study included 13 participants, 11 of whom completed the trial. Ten of these participants were found to have significant improvement in their symptoms. Unfortunately, a study carried out on such a small number of people cannot be taken as conclusive evidence that SAMe could be used as a treatment for depression in Parkinsons. No larger study has been carried out to support this finding. NADH Some media reports have advocated the use of an antioxidant compound called NADH (Nicotinamide Adenine Dinucleotide, sometimes known as ENADA) in the treatment of Parkinsons. Only one trial has been carried out and this reported no improvement in the participants condition following administration of the drug.10

A small study on a mouse model of Parkinsons did demonstrate that treatment of Sources of NADH in the diet include liver, mice with levodopa for up to six days altered poultry, fish, peanut butter, legumes, milk and the levels of SAMe, but that these levels eggs, and it is also available in supplement form. returned to normal after a short period of time.8 While this does suggest that SAMe may be involved in the action of levodopa, it does not 9 suggest that SAMe supplements would help Di Rocco A et al (2000) S-Adenosyl-Methionine improves
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Liu X et al (1998) L-dopa depletes S-Adenosylmethionine and increases S-Adenosyl homocysteine: Relationship to the wearing-off effects Society for Neuroscience Abstracts; 24: 1469

depression in patients with Parkinsons disease in an open-label clinical trial Movement Disorders; 15(6): 12251229 10 Dizdar N et al (1994) Treatment of Parkinsons disease with NADH Acta Neurol Scand;. 90: 345347.

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Fermented papaya supposedly has potent antioxidant properties and we have asked the PDSs scientific advisers for their opinion. They say it is impossible to comment because they do not know what is in the extract, or how it might interact with an existing drug regime. For example, papaya contains digestive enzymes that contain amino acids. It is known that some amino acids can interfere with the absorption of Alpha-lipoic acid levodopa from the small bowel. There is a need Alpha-lipoic acid is another antioxidant that for caution until more is known, and the PDS is produced in small quantities by the body. It cannot recommend this treatment on the basis has the added benefit of being able to recycle of current knowledge. other antioxidants, and it has also been Some press reports have also stated that claimed that alpha-lipoic acid may be able to the papaya extract is available in health food elevate the levels of glutathione in the brain, shops as chewable papaya enzyme. Please which would make it of particular interest for note that this is not the same as the extract Parkinsons. However, the effects of alphathat the Pope was supposedly taking. The lipoic acid supplementation on Parkinsons PDS would not recommend anyone with have not been properly studied. Parkinsons to take papaya or any other antioxidant without discussing this further with Fermented papaya extract In the past; there has been some interest in the their doctor. While it is true that NADH is found naturally in the body and is vital in many energy-producing reactions, these reactions are most unlikely to be affected by NADH taken orally, as it is unlikely that the drug will reach the brain. As yet, it is impossible to truly assess the action of the substance being taken, in the context of Parkinsons. media concerning the supplement ImmunAge, which contains fermentated papaya extract, allegedly taken by the late Pope John Paul II. Reports suggested that the Pope was taking this fermented papaya extract, and that it had a marked benefit on his symptoms. Any observations made about the Pope were particularly difficult to confirm since no information was available concerning his symptoms or what drug treatment he was taking, if any. It is very difficult to comment on the effects of one supplement alone when any number of factors might account for a noted improvement, such as a change or addition to an existing drug regime, or treatment for another condition or illness that he may have had. Should I be taking vitamin supplements? Many of the chemicals discussed above can be found in supplement form, either individually or as part of a multivitamin supplement. There are a number of other important antioxidant chemicals, many of which can be found in multivitamin supplements: vitamin C (ascorbic acid) and selenium, for example. Most of these have not in themselves been studied for their effects on cell death in Parkinsons. It has been argued that compounds such as vitamins C and E actually perform better in combination with each other. However, it has not yet been shown that multivitamins or individual antioxidant supplements have any specific effect on

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Parkinsons, and the PDS is unable to recommend specific brands or dosages. However, if you feel that your diet is not providing you with enough of the essential vitamins and minerals, then a vitamin supplement may be of use to you but should first be discussed with your doctor or dietician. Any form of supplement or treatment should only be taken in addition to drug treatments for Parkinsons and not as an alternative. More information on diet is available in the booklet Parkinsons and Diet. Further information This information sheet refers to a number of articles that report on scientific research into the role of antioxidants in Parkinsons. The PDS is unable to supply copies of these articles. Your local library should be able to help you locate copies. Alternatively, for summaries of each of these studies, visit the PubMed website at www.ncbi.nlm.nih.gov/ entrez/query.fcgi The US Food and Drug Administrations Center for Food Safety and Applied Nutrition

has produced a guide for people who are interested in supplementing their diet with vitamins, herbal remedies, etc. The guide, entitled Tips for the Savvy Supplement User, is available at the following website: www.cfsan.fda.gov/~dms/ds-savvy.html Acknowledgements We would like to thank Dr David Dexter and Dr Ronald Pearce for their help with reviewing this information sheet.

Parkinsons Disease Society 215 Vauxhall Bridge Road, London SW1V 1EJ, UK Tel: 020 7931 8080 Fax: 020 7233 9908 Helpline: 0808 800 0303 Text Relay: 18001 0808 800 0303 (for textphone users only). (The Helpline is a confidential service. Calls are free from UK landlines and some mobile networks) Email: enquiries@parkinsons.org.uk Website: www.parkinsons.org.uk Parkinsons Disease Society of the United Kingdom (2008) Charity registered in England and Wales No. 258197 and in Scotland No. SC037554. A company limited by guarantee. Registered No. 948776 (London) Registered office: 215 Vauxhall Bridge Road, London SW1V 1EJ Revised November 2008 To obtain any of our resources, please go online to www.parkinsons.org.uk or contact Sharward Services Ltd, the appointed Distribution House, at Westerfield Business Centre, Main Road, Westerfield, Ipswich, Suffolk IP6 9AB Tel: 01473 212115 Fax: 01473 212114 Email: parkinsons@sharward.co.uk
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