After more than 12 month’s research and experimentation, a small group of Parkinson’s disease patients successfully carried out a 6-week study using a specially prepared Broccoli seed tea to reduce oxidative stress in neurons. This post gives the scientific context to the study and explains WHY they decided to try out this potentially disease-modifying therapy which has not been officially approved.
“Pilot study of broccoli seed tea by Parkinson’s Patients”
This article is now available in PDF format on the Documents page
If you prefer to learn about HOW this study was carried out and the results obtained, go to the “The broccoli seed tea experiment”. You can find this post here.
Albert F Wright, PhD
Introduction: Compelling evidence by leading researchers supports the hypothesis that a contributing factor in the aetiology of Parkinson’s disease is age-related divergence from normal redox balance in brain cells. This divergence allows excessive oxidative stress and inflammation to damage cells and disrupt neuronal function. The equilibrium between oxidants and antioxidants is controlled by the transcription factor Nrf2, the master regulator of antioxidant responses. The the activity of Nrf2 declines with age, leading to greater levels of oxidative stress.
The isothiocyanate sulforaphane, which can be made from broccoli seeds is able to activate Nrf2, and modify the redox balance.
After being diagnosed with Parkinson’s disease in 2018, I decided to explore this idea by monitoring my own symptoms in response to treatment by a specially-prepared broccoli seed extract. After 12 months of experimentation, I shared my observations and methods with a small number of Parkinson’s patients who were interested in testing the method for themselves. This is their story.
This hypothesis had never been tested for Parkinson’s disease in official clinical trials, but now a small group of Parkinson’s disease patients have demonstrated by their own efforts that a broccoli seed tea containing sulforaphane can improve their symptoms of Parkinson’s disease. This new study clearly shows that non-motor symptoms are strongly attenuated by this treatment whereas motor symptoms remain unchanged over the timescale of this experiment.
The Redox Balance System
Over the last 20 years highly-specialised research has demonstrated how cells use a gene-based system to maintain the balance between oxidants and antioxidants within a healthy range inside cells. We now believe that the set-point of this redox control system can drift out of the healthy range as we get older, opening the door to many chronic illnesses such as neurodegenerative diseases, cancer, heart disease etc. This Redox Balance System (RBS) can affect all cells, but is most active in brain, heart, urinary tract, gastrointestinal tract and endocrine tissues. It’s first job is to detect and rapidly destroy any excess oxidizing molecules and free radicals (Reactive Oxygen Species (ROS) and Reactive nitrogen Species (RNS)) as well as toxins that can damage cell membranes, mitochondria and DNA. ROS and RNS are automatically generated when cells make energy from glucose and oxygen. Brain cells, especially dopamine-producing brain cells, use more energy and create more ROS than other cells. The second job of the RBS is to fight excessive inflammation. Too much ROS and inflammation is bad for cells, but so is too little, since ROS and inflammation are the first linea of defence against infection and cancer. The RBS has built-in control processes to adjust ROS and inflammation up or down to meet changing conditions. There is however clear evidence, that in brain cells of people with Parkinson’s disease this system fails to keep ROS and inflammation within the healthy range at all times.
For a full scientific explanation of the mechanisms involved and how Brassica seed extracts can be used to combat the causes of Parkinson’s disease, click on the following link: Role of the transcription factor Nrf2 and Redox Balance in Parkinson’s Disease
For the scientific community, the RBS is called the Nrf2/Keap1/ARE pathway, after the 3 key players in this process. Don’t worry about the names, they are acronyms for the 3 proteins which have a specific function in maintaining the redox balance:
- ARE (Antioxidant Response Elements) are enhancer sequences in promoter regions of the DNA of every chromosome. When activated, they initiate the mechanism to promote the transcription of groups of genes that express antioxidants, antioxidant enzymes and anti-inflammatory cytokines to combat oxidative stress and inflammation.
- Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) are signalling molecules (transcription factors) that locate to ARE and switch it on by binding to it.
- Keap1 (Kelch-like ECH-associated protein 1) is the gatekeeper protein that regulates the flow of Nrf2 to ARE. It does this in response to signals from 27 sensors incorporated in the protein that detect the presence of ROS, RNS, toxins and electrophiles in every cell.
Under stable conditions, Nrf2 protein binds to docking sites of the protein dimer Keap1 in the cytoplasm and is degraded. When Keap1 is oxidised by ROS, electrophiles or sulforaphane, newly synthesised Nrf2 then migrates to the nucleus where it binds to ARE and promotes the transcription of antioxidant and anti-inflammatory genes. Illustration adapted from P. Hiebert and S Werner.
Whenever Nrf2 binds to ARE, the gene promoter function of ARE initiates the transcription of a battery of genes to produce antioxidant and detoxifying enzymes, anti-inflammatory cytokines and simultaneously suppresses inflammatory cytokines. Cytokines are small messenger proteins that generate or suppress inflammation. The function of these genes is to restore a healthy environment inside each and every cell to enable them to function correctly. The rate of production of these antioxidant and anti-inflammatory elements depends on the quantity of Nrf2 present in the nucleus close to ARE promoters. In dopamine brain cells of people with Parkinson’s disease, ARE promoters do not receive enough Nrf2 to restore this healthy environment. One way to resolve this is to subdue the activity of the gatekeeper Keap1, so that more Nrf2 protein can reach ARE and increase the expression of antioxidant molecules and enzymes. There are several natural molecules found in foods that are known to reduce the activity of Keap1, but they are not present in normal food in sufficient quantities to resolve this problem.
Calming down the Keap1 gatekeeper
It takes 2 molecules of Keap1 to form a dimer which can capture one molecule of Nrf2. Keap1 molecules are judges and administrators of the redox environment. They judge the levels of ROS in the cell using 27 different sensors that detect the presence of oxidants and toxins. The higher the levels of ROS detected, the more Nrf2 molecules get a free passage to relocate to the nucleus where they can switch on ARE and boost the production of antioxidant enzymes and anti-inflammatory cytokines. If the levels of ROS are judged to be low or satisfactory, the Nrf2 molecules are detained and destroyed by keap1. The process is designed to keep the level of enzymes and cytokines at the optimum level to maintain a healthy environment. For people with Parkinson’s disease, the RBS fails to maintain the optimum redox balance and levels of ROS are allowed to drift too high. The RBS controler needs to be adjusted to bring the ROS balance back into the range that keeps neurons healthy.
A partial explanation for the excessive levels of ROS may simply be found n the process that drives natural ageing. As we get older, our cells produce less Nrf2 and more Keap1. This altered ratio means that the flow of Nrf2 molecules to ARE is reduced such that ARE gets switched on less frequently, moving the redox range to a higher state of oxidative stress. Fortunately, we now know how to calm down Keap1 so that more Nrf2 can reach ARE. We must however be careful not to be too heavy-handed. If we increase Nrf2 too far or too fast the system is designed to react against such excesses and will automatically activate a negative feedback loop creating the opposite effect, albeit with a delay.
One way to calm down Keap1 is to supply it with “soft oxidant” molecules called electrophiles. Oxidation is the process whereby an atom or molecule loses an electron by transferring it to another atom or molecule. Strong oxidants like ROS, aggressively and permanently steal electrons from other tissues, a process that damages them. Electrophiles, on the other hand, are more moderate and temporarily “borrow” electrons. Electrophiles are strongly attracted to some of the Keap1 sensors which have electrons to lend. When a Keap1 sensor lends an electron this triggers the process to inactivate its gatekeeping function. The most active electrophiles in foods are found in cruciferous vegetables such as cabbage, broccoli, Brussels sprouts, mustard, and turnips. Isothiocyanates are what give these vegetables the reputation of being healthy foods, but are also responsible for their strong taste which some people find unpleasant. There are more than 100 different isothiocyanates in these plants, but the one we are most interested in is called sulforaphane and is present in broccoli. It is found in high concentrations in the seeds or sprouts (early seedlings). The vegetable only contains small amounts.
Can resetting the redox balance help Parkinson’s disease?
Resetting the redox balance system has not been officially tested on humans with Parkinson’s disease. In 2010, a leading neurologist, Dr Antonio Cuadrado proposed a Phase II trial using sulforaphane to reduce oxidative stress for Parkinson’s disease, in a human trial supported by 16 European hospitals. The Michael J. Fox Foundation for Parkinson’s disease turned down his request for funding. The reason given was:
“If it would show a relevant efficacy, no company would be interested in covering the huge cost of a Phase III trial for a natural compound that could not be patented.”
Put another way – “Well, even if it would benefit Parkinson’s patients, we will not support it since there is no financial incentive for pharmaceutical companies to develop such a therapy.” Over the ten years since this statement and despite considerable progress by researchers, no pharmaceutical company has shown any interest in using sulforaphane to treat Parkinson’s disease.
What can Parkinson’s patients do to break this deadlock?
Waiting will not help Parkinson’s patients!
The passive approach is to wait for pharmaceutical companies to synthesise and test new molecules that will do the same job as these natural isothiocyanates. Unlike natural molecules, synthetic ones can be patented and their potential revenue from drug sales can therefore be protected. Work on synthetic electrophiles started before the end of the last century, well before the Nrf2/Keap1/ARE pathway was fully understood. There are now many different synthetic molecules being tested for different conditions, but none for Parkinson’s disease. However, even if these synthetic molecules were proven to be effective for the treatment of Parkinson’s disease, it will take at least 10 years before they become available to patients.
Getting involved improves your knowledge and gives you a voice
The active approach is for Parkinson’s patients to test for themselves whether natural isothiocyanates could have an effect on their own symptoms. My own experiments and observations enabled me to set up a protocol for the preparation and dosing of Brassica seed extracts and a checklist for following up the evolution of symptoms over a period of weeks or months. This protocol, although far from perfect, was made available to a group of Parkinson’s disease sufferers in October 2020. A small number decided to try it out for themselves by following a program of self-experimentation, making their own broccoli tea and pooling their data. The results from this pioneering experiment are quite remarkable. They clearly show that a specific group of symptoms, collectively called non-motor symptoms respond strongly to this treatment over a period of just a few weeks, whereas motor symptoms remain practically unchanged over this short timescale.
Non-motor symptoms were strongly attenuated by broccoli seed tea whereas motor symptoms were largely unaffected.
Interesting, but what does this mean?
Sceptics may say that this experiment wasn’t a proper double-blind trial with a placebo arm, so it’s probably just a placebo effect and doesn’t mean anything. So let’s check that out. There has been a lot of research on the placebo effect in PD. It turns out that when PD patients are given a placebo, but they think it might be the real drug, they get a positive effect. Because of the “expectation” that the drug may do some good, they think positive and their neurons make more dopamine. Great, and what does this extra dopamine do? Well, the extra dopamine makes movement easier and attenuates motor symptoms. That makes sense, but in this case motor symptoms were not improved, but the non-motor symptoms were improved. Well, so maybe there is some other explanation.
General fatigue was the most widespread non-motor symptom among the 8 PwP who took part in the experiment. All participants reported suffering from general fatigue and all 8 reported improvement or remission from fatigue at the end of the 6-week experiment. The total fatigue score was reduced by 90%. So let’s take a closer look at fatigue
Persistent fatigue, an overwhelming sensation of exhaustion unrelated to physical effort, is one of the earliest and most common symptoms reported by Parkinson’s disease patients, often occurring well before diagnosis and remaining throughout its progression. Fatigue has a major impact on quality of life of PD patients, but remains one of the least documented and least researched symptoms of PD. Fatigue is also a hallmark symptom of mitochondrial disease and markers of elevated oxidative stress and mitochondrial dysfunction correlate with disease severity of patients diagnosed with Chronic Fatigue Syndrome.
Taken together with previous knowledge, the results of this experiment are consistent with a more refined model in which mitochondria in dopaminergic neurons are the primary target of oxidative stress leading to compromised energy production in DA neurons.
Given the wealth of experimental data relating oxidative stress to mitochondrial dysfunction and compromised energy production in DA neurons, the omnipresence of fatigue reported by Parkinson’s disease patients is unsurprising. The remarkable attenuation of fatigue by the participants in the broccoli seed tea experiment is consistent with the hypothesis that sulforaphane, by upregulating the Nrf2/ARE pathway and neutralising oxidative stress is active in reducing mitochondrial dysfunction and restoring normal energy production in neurons. The relative rapidity of the effect also appears to be consistent with the dynamics of mitochondrial evolution and regeneration.
A theory for PD based on a cascade of 2 mechanisms
If the above hypothesis is correct, then it would appear that Parkinson’s disease progresses via 2 distinct steps.
Step 1: Oxidative stress creates mitochondrial dysfunction and reduced energy production
With increasing redox imbalance, oxidative stress damages mitochondria in highly-exposed neurons. This impairs the Complex 1 enzyme in mitochondria which is an essential enzyme in the process to make energy from glucose and oxygen. Reduction in Complex 1 automatically creates more ROS and sustains a vicious circle which amplifies the process. These neurons suffer an acquired but reversible version of chronic mitochondrial dysfunction through oxidative stress. The hallmark symptom of mitochondrial dysfunction is fatigue, a common non-motor symptom of Parkinson’s disease. Dopaminergic neurons are among the most highly exposed because of their high energy demands, but other neuron types are also very likely to be affected.
Step 2: Energy deficient DA neurons cannot sustain their normal dopamine production.
As their energy supply declines, an increasing number of DA neurons become less productive and may even shut down altogether. Some may eventually die. Dopamine availability will then decline to below the critical threshold for normal motor function, causing the appearance of motor symptoms. There is every reason believe that this cascade of events will continue as the disease advances.
A disease which progresses by 2 distinct mechanisms requires a therapeutic approach to address both steps. Current therapies only address the dopamine deficit which is responsible for motor symptoms of Parkinson’s disease. There is an urgent need to respond to mitochondrial dysfunction and the energy deficit acquired through oxidative stress to Complex 1 enzymes in all types of neurons.
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Albert F Wright