Resolving Mitochondrial Dysfunction to attenuate non-motor symptoms of PD

My research is focused on stopping the processes that damage and destroy dopamine-producing neurons. These are the earliest processes in the chain of events causing Parkinson’s disease.

The objective of this research was to activate the transcription factor Nrf2 (nuclear factor erythroid-2-related factor 2) as a means of stopping oxidative stress and mitochondrial damage in neurons. These processes are involved in a vicious circle that generates increasing amounts of ROS and increases the damage to the processes by which mitochondria make energy inside the neurons that make dopamine. The reduced energy production and increased ROS, reduces the capacity of these neurons to produce and deliver dopamine to more distant regions of the brain. This damage inside neurons is the very first step in the development of Parkinson’s disease. However, this may go unrecognized for many years because the symptoms it creates (fatigue and other non-motor symptoms), can also be attributed to conditions due to age rather than to Parkinson’s disease. Any dopamine shortage in more distant brain regions reduces the capacity of these regions to function properly. The brain adapts to this situation by making new connections reduce the workload of the affected regions but this solution is imperfect and leads to the development of clusters of neurons that function synchronously rather than individually and cause motor symptoms. At the point of diagnosis, both of these conditions (damage inside neurons and clusters of synchronized neurons) are present and progress simultaneously.

Targeting the causes of this early-stage damage to dopamine-producing neurons is driven by several objectives:

1. To reduce and eventually eliminate the chronic state of stress and fatigue of dopaminergic neurons and attenuate the symptoms caused by this chronic state,
2. To improve the energy-producing capacity of these neurons by renewing damaged mitochondria,
3. To improve the redistribution of dopamine to those parts of the brain that are suffering dopamine shortage,
4. To enable dopamine neurons to repair damage by regrowing the axon arborescence,
5. To prevent further damage to the more distant brain regions.

The first 3 of these changes involve molecular reactions and internal cellular operations, including neutralizing oxidative stress (with timescales of seconds) and restoring mitochondrial function (with a timescale of days). These changes could therefore have a positive impact on the quality of life of People with Parkinson’s over the relatively short timescales.

The fourth objective will require cellular repair and regrowth of axons and synapses. These processes may be only partially achievable may take longer to complete than the timescale of the proposed experiments.

The fifth may have a purely preventative role, with no observable effects over the timescale of our experimentation.

The Optimisation of Broccoli Seed Tea

A major step in the development of a reliable source of sulforaphane.

After more than 3 years focused on validating the Keap1/Nrf2/ARE pathway and its impact on Parkinson’s disease, combined with practical laboratory research to develop a standardized broccoli seed tea (BS1312) to activate the Nrf2 pathway, this research is now approaching maturity.

The Keap1/Nrf2/ARE pathway was abandoned by the pharmaceutical industry more than a decade ago, not because of doubts about its potential efficacy, but because its profitability could not be assured. Since plant-based molecules cannot be protected by strong patents, projects based on natural molecules are often considered by commercial drug companies to be unprofitable, irrespective of any potential medical benefit for patients. Research by leading scientists, provides convincing evidence that activating the Keap1/Nrf2/ARE pathway could deliver benefit as a disease-modifying therapy for Parkinson’s disease patients. This hypothesis was tested for 30 months using an extract of broccoli seeds containing sulforaphane, the most potent natural activator of the the transcription factor Nrf2. During that time, research into the biological and chemical processes involved in the conversion of glucoraphanin to sulforaphane led to progressive improvements in the quality of the broccoli seed tea and the development of BS1312.

The second phase was launched in October 2022 with a pilot study of the impact of a BS1312 on Urinary Urgency in Parkinson’s disease. Other symptoms having a strong impact on quality of life were also monitored. Preliminary results are demonstrating the remarkable efficacy of BS1312 to concomitantly attenuate a wide range of non-motor symptoms of Parkinson’s disease. We invite everyone with an interest in Parkinson’s disease to support this project financially.

We use a unique source of high-quality seeds in our research

The seeds of broccoli (Brassica oleracea var. italica), contain glucoraphanin, the precursor of sulforaphane. There are many varieties of broccoli which have been developed by crossing broccoli with other brassica species to improve yield or resistance to pests. As a result the glucoraphanin content of broccoli seeds varies depending on the variety, but the actual glucoraphanin content is rarely known. Indeed, some special varieties of broccoli, especially those intended for growing sprouts, do not belong to the Brassica oleracea var. italica species and the seeds contain no glucoraphanin at all.

To avoid this problem, we procured a stock of broccoli seeds with a high, quantified glucoraphanin content for use in our research. These seeds are not for sale and are not commercially available to the general public. However, some commercially-available broccoli seeds can be used to make good quality Broccoli Seed Tea.

The preparation of high-quality Broccoli Seed Tea

Broccoli Seed Tea is a great way to make fully bioavailable active sulforaphane. Making sulforaphane from broccoli seeds involves some complex biological and chemical reactions.

To make sulforaphane we must first extract the glucoraphanin into solution in hot water. We then follow this by adding a prepared solution containing an enzyme called myrosinase, which can break the GR by cutting the S-bond that binds the glucose molecule and liberates it. Temperature control is critically important.

The result of the hydrolysis reaction is an unstable intermediate molecule [shown in brackets]. This intermediate molecule then rearranges to make either sulforaphane, or a nitrile, a molecule that is not biologically active. a number of parameters must be respected to obtain a good yield of sulforaphane in the final reaction. Our research has resulted in identifying the optimum conditions to make high-quality broccoli seed tea reliably. These conditions are incorporated into the BS1312 Protocol.

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