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Neuroprotection

Slowing down or even stopping the process of neurodegeneration remains one of the most important goals and a key unmet need in contemporary research of Parkinson’s disease.

The term neuroprotection – from the Greek word ‘neuron’, meaning nerve cell, and ‘protection’ – refers to mechanisms and strategies within the nervous system which protect neurons from degeneration, and enable their recovery and restoring of their functions. In the context of Parkinson’s, neuroprotection refers to any intervention which delays or prevents the death of dopamine-producing cells and, therefore, slows or halts disease progression.

Neuroprotective agents may be specifically developed pharmacologic substances, but also substances such as caffeine seem to have a potential to preserve our brains from neurodegeneration.

Neuroprotection and Parkinson’s

Slowing down or even stopping the process of neurodegeneration at early stages remains one of the most important goals of current Parkinson’s research.

For many years, research in Parkinson’s mainly focused on novel therapies that could improve symptoms of the disease. However, in contemporary trials, scientists increasingly aim to gain new insights into the causes and progression of Parkinson's that may, in the future, lead to the development of disease-modifying agents and change the natural progression of the condition. The hope is that specific neuroprotective agents can be developed and intervene in some of the processes leading to cell death and so protect the remaining neurons. : Some of the possible substances that may have neuroprotective abilities are the following:

  • anti-oxidant – scavenging any harmful free-radicals that may cause cell damage
  • anti-inflammatory – preventing harmful inflammation
  • anti-apoptotic - preventing the self-destruction of cells
  • anti-excitotoxic - preventing the process by which nerve cells are damaged and killed by various substances
  • pro-mitochondrial - supporting the mitochondria which provide cells with energy.

Neuroprotection is a highly specific area of research so your doctor or neurologist may not have detailed knowledge but will be able to refer you to a specialist who can provide more information.

Physical activity and exercise is the best currently known neuroprotection strategy. Similarly, it is generally agreed that keeping your brain as active and challenged as possible helps it to stay healthier for longer. Doing puzzles such as Sudoku and crosswords, or mental arithmetic rather than using a calculator, really can help your brain function better, as can stimulating conversation and reading.

Research

Various clinical trials are under way on a number of compounds in laboratory studies. Although many of the findings look promising there has been some controversy over the interpretation of results. This is partly due to the considerable difficulty in both designing appropriate trials and establishing effective markers and methods to evaluate the neuroprotective benefits of compounds.

It is also now recognised that Parkinson's may start long before the classic motor symptoms, such as tremor, bradykinesia and stiffness, are obvious. This is known as the prodromal stage of Parkinson's in which non-motor symptoms, such as reduced sense of smell, sleep problems, sleepiness or constipation, may be most noticeable. The challenge is to start neuroprotectiive measures at this stage to maximise the potential number of cells that can be saved.

Of note, while numerous pharmacological therapeutic strategies are available to treat the dopamine deficiency in patients with Parkinson’s and have been shown to improve motor symptoms, no drug has yet been shown to slow the progression of the loss of dopamine cells1.

References

  1. Ahlskog JE, Uitti RJ. Rasagiline, Parkinson neuroprotection, and delayed-start trials: still no satisfaction? Neurology 2010 Apr 06. Vol. 74(14); 1143–1148 – view abstract

Potential neuroprotective agents

Anti-oxidants

There is a growing interest in the role of free-radical damage in Parkinson’s and other conditions. Free-radicals in moderation are normal but if there are more than the body can cope with, a condition called oxidative stress occurs; its role in the death of dopaminergic neurons in Parkinson’s disease has been shown in several studies​. 

Anti-oxidants, both as supplements and in naturally occurring forms, have the ability to scavenge and neutralise free-radicals. Most scientists agree that the brains of people with Parkinson’s have too many free-radicals and not enough anti-oxidants to balance them out. Whilst anti-oxidants are no cure for the condition, many hope that they can help to slow the progression of Parkinson’s. However concrete scientific data to back up claims is limited and comes only from animal studies1. You should always discuss with your doctor before taking any supplements.

It is thought that certain Parkinson’s medications may have anti-oxidant properties and more research is underway to establish if this is the case.

References

  1. Filograna R, Beltramini M, Bubacco L, Bisaglia M. Anti-Oxidants in Parkinson's Disease Therapy: A Critical Point of View. Current Neuropharmacology 2016. Vol. 14(3); 260–271 – view abstract

MAO-B inhibitors

Perhaps the simplest and most important theory relating to neuroprotection in Parkinson's is that dopaminergic treatment, which supports the degenerating cells, can provide significant long term neuroprotective benefits if started in the early stages of Parkinson’s.

A study on the MAO-B inhibitor rasagiline1 indicates that people with Parkinson’s who received this treatment earlier had a better outcome than those whose treatment was delayed. According to this study, starting medication soon after diagnosis provides some long term neuroprotection through a compensatory mechanism that may preserve the remaining dopaminergic neurons. Further research is needed to improve our understanding of this compensatory mechanism.

Several studies concerning selegiline, another MAO-B inhibitor, indicate that it too might have neuroprotective actions although more research into this is still needed (DATATOP2).

However, this topic remains controversial, since it is difficult to distinguish symptomatic effects from a true effect on disease progression3, and since many of the drugs proposed to slow progression improve dopaminergic neurotransmission and treat Parkinson's symptoms.

See also MAO-B inhibitors.

References:

  1. A randomized, double-blind, placebo-controlled, delayed start study to assess rasagiline as a disease modifying therapy in Parkinson's disease (the ADAGIO study): Rationale, design, and baseline characteristics - view abstract
  2. The Parkinson’s Study Group (1993) ‘Effects of Tocopherol and Deprenyl on the Progression of Disability in Parkinson’s Disease’ New England Journal of Medicine; 328: 176–183 - view abstract.
  3. Ahlskog JE, Uitti RJ. Rasagiline, Parkinson neuroprotection, and delayed-start trials: still no satisfaction? Neurology 2010 Apr 06. Vol. 74(14); 1143–1148 – view abstract

Dopamine agonists

In animal models of Parkinson’s, Pramipexole showed neuroprotective abilities.

The PROUD study1,2 was the first to combine early versus delayed pramipexole treatment to investigate the potential clinical benefits of early treatment. However, although pramipexole is an effective medication in relieving Parkinson’s symptoms, the results of the study were not conclusive and it failed to show that early treatment modifies the progression of Parkinson’s.

See also Dopamine agonists

References:

  1. Rationale for delayed-start study of pramipexole in Parkinson's disease: the PROUD study – view abstract
  2. Schapira AH, McDermott MP, Barone P, et al. Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial. The Lancet Neurology 2013 Aug 01. Vol. 12(8); 747–755 – view abstract

Vitamin C and E

Some scientists supported the view that the anti-oxidants vitamin C and vitamin E may have some neuroprotective abilities in Parkinson’s. However, clinical trials failed to show any efficiency of Vitamins C and E in slowing the progression of Parkinson’s1.

References:

  1. Parkinson Study Group, Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The New England Journal of Medicine 1993 Jan 21. Vol. 328(3); 176-83 – view abstract

Creatine

Creatine is a dietary supplement which is often taken by athletes to improve their performance. It is thought that creatine may act as an indirect anti-oxidant by storing energy and protecting against neuronal cell death. Additional studies and research into this are required to better understand if creatine could play a role in neuroprotection.

Co-enzyme Q10

Coenzyme Q10 (CoQ) is a fat-soluble anti-oxidant compound found in every cell of the body, as well as in a number of foods. Brain levels of CoQ fall with age and are likely to be significantly lower in people with Parkinson’s. Small studies have suggested that CoQ scavenges free-radicals more effectively than vitamin E. However, a large, multicentre, placebo-controlled study including 600 patients who received high-dosage CoQ10 treatment did not show any clinical benefit of this substance1.

References:

  1. The Parkinson Study Group QE3 Investigators, A Randomized Clinical Trial of High-Dosage Coenzyme Q10 in Early Parkinson Disease – No Evidence of Benefit. JAMA Neurology 2014 May. Vol. 71(5); 543-552 – view abstract

Non-steroidal anti-inflammatory drugs (NSAID)

Non-steroidal anti-inflammatory medication, such as ibuprofen and aspirin, have been shown to have some neuroprotective abilities in animal models of the disease1. NSAIDs are also naturally present in certain foodstuffs, including turmeric and curcumin. Curcumin is the main active ingredient of turmeric, the most important compound in most curry powders. Like green tea, it belongs to a group of compounds called polyphenols, many of which we now know have health benefits in humans.

References:

  1. Hirsch E, Hunot S. Neuroinflammation in Parkinson's disease: a target for neuroprotection? The Lancet Neurology 2009 Apr 08. Vol 8(4); 382–97 – view abstract

Curcumin

Curcumin is the subject of various research studies into its potential benefits, including anti-oxidant and anti-inflammatory properties. These are thought to reduce oxidative damage in the brain, and therefore slow or reverse the progression of Parkinson's, with reduced side effects and toxicity compared to other NSAIDs. It has been estimated that in the US and UK 280 out of 100,000 people develop Parkinson’s whilst in India the rate is as low as 14 per 100,000, leading to speculation that curcumin may be a factor in reducing brain cell damage. Some hypothesise that if turmeric can protect foodstuffs from oxidative degradation, it can perhaps act in a similar way for our bodies, as may other natural NSAIDs. Again, this is an area of ongoing research and the potential neuroprotective abilities of curcumin are yet to be shown.

Other potential neuroprotective factors

There are a number of lifestyle choices and nutritional substances that appear to be neuroprotective, such as coffee drinking, cigarette smoking (obviously within sensible limits and with the obvious health caveats) and ginseng. Further studies need to be conducted to establish the extent of any correlation between these and Parkinson’s. It is important to remember that any neuroprotective effect have not been proofed in humans yet. It is generally unwise to consume large quantities of a particular product as this can in itself cause health problems.

Caffeine

Research1 has shown that coffee drinkers who have a daily intake of caffeine of approximately 100 mg, i.e. the amount you might expect in a cup of espresso or a cappuccino, develop Parkinson’s less frequently. 

In studies to induce Parkinson’s in animals, caffeine was seen to protect those given the stimulant. A study at the Honolulu Heart Program in Hawaii2 found that the likelihood of developing Parkinson’s was five times greater in men who did not drink coffee compared to those who had at least 28 grams of coffee a day. The men who drank the most coffee had the most reduced risk of developing the condition.

Caffeine is also present in other foodstuffs such as green tea, black tea, chocolate and soda. Consuming these also appears to have a neuroprotective effect.

Whilst some studies seem to suggest a link between caffeine and Parkinson’s, it is perhaps premature to suggest that caffeine will prevent the condition and it should be remembered that coffee can cause insomnia and anxiety and may affect blood pressure. It could be that the brains of people who like to drink coffee differ from those who do not and that this difference results in the varied incidence of Parkinson’s in relation to coffee consumption.

Polyphenols

Polyphenols are naturally occurring anti-oxidants found, for example, in green tea and tangerines. In a rat model of Parkinson’s disease, these chemicals have been shown to improve the flow of dopamine between different parts of the brain and could help to slow the loss of dopamine-producing cells. Laboratory studies into polyphenols and Parkinson’s have been carried out in mice, but further studies on tea-drinking in humans are required. For example, one epidemiological study in the Chinese population demonstrated that black tea drinking reduced the risk of Parkinson's3. It should be noted that over-consumption of green tea can interfere with the absorption of iron by the body and may cause stomach upsets so you should discuss this with your doctor.

Smoking

Whilst we do not endorse or advocate the smoking of cigarettes because of the many health risks associated with it, epidemiological studies have consistently suggested a link between cigarette smoking and Parkinson’s, leading to theories that smoking – in particular nicotine – may be neuroprotective. In animal studies nicotine has been found to stimulate the release of dopamine in the brain and to preserve neurons and dopamine levels.

One study4 found that former smokers had a 22% lower risk of developing Parkinson's and current smokers had a 73% lower risk compared to those who had never smoked and were thought to have a ‘normal’ risk for developing the condition. In fact, there appears to be a correlation between the risk of developing Parkinson’s and the number of years of smoking, the number of years since stopping smoking and the number of cigarettes smoked per day.

Ginseng

Ginseng has been used for centuries as a traditional Chinese herbal remedy and today it is widely thought to possess neuroprotective and neurotrophic properties, which may be useful in preventing the degeneration of dopamine-producing cells. 

Studies are now underway to better understand if and how ginseng can protect against the condition. In Halifax, Nova Scotia, Canada, in 2004, neuroscientists fed ginseng to rats in their drinking water and then injected them with a powerful toxin MPP+ known to usually induce Parkinson’s in animals. But unusually the rats did not develop the condition, so the researchers concluded that the ginseng had somehow protected their neurons.

Whilst the results are promising, questions remain as to how ginseng works and scientists are trying to establish which components of ginseng have neuroprotective properties so that more powerful medications can be made.

References:

  1. Leiden University: Coffee and Parkinson's - view abstract
  2. Association of Coffee and Caffeine Intake With the Risk of Parkinson Disease - view abstract
  3. Chan DK, Mellick GD, Hung WT, Woo J, Genetic and environmental risk factors and their interactions for Parkinson's disease in a Chinese population. Journal of Clinincal Neuroscience 2003 May. Vol. 10(3); 313-315 – view abstract
  4. Temporal relationship between cigarette smoking and risk of Parkinson disease - view abstract.

Content last reviewed: February 2020

Acknowledgements

We would like to thank Prof K. Ray Chaudhuri DSc FRCP MD (King’s College London and King’s College Hospital, London, UK) for his help in reviewing this information.

Related reading

  • Study links smoking, reduced Parkinson’s risk, but comes with caveat
  • Drinking coffee may reduce your chances of developing Alzheimer's, Parkinson's

Articles from Parkinson's Life online magazine

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