The Human Parkinsonian Neurotoxin 1
In the early 1980s, several drug users from Northern California developed an acute state of akinesia following the intravenous injection of a street preparation of 1-methyl-4-phenyl-4-propionpiperidine , an analog of the narcotic meperidine. After fine detective work, it was found that MPTP, which was inadvertently produced during the illicit synthesis of MPPP, was the culprit behind this dramatic clinical picture. The chemical structures of MPPP and MPTP are shown in .
Comparison of chemical structures of MPPP and MPTP.
The Neurotoxic Herbicide Paraquat
The potent herbicide paraquat is another prototypic toxin known to exert deleterious effects through oxidative stress. Indeed, as reviewed elsewhere, paraquat toxicity is mediated by redox cycling with cellular diaphorase such as nitric oxide synthase, yielding ROS. As detailed, the actual reduction-oxidation cycling reaction of paraquat can thus be depicted in . Thus far, there have been several cases of lethal poisoning resulting from ingestion or dermal exposure. For many years, experimental studies using paraquat were focusing on its effects on lung, liver, and kidney probably because the toxicity induced by this herbicide in these organs is responsible for death after acute exposure. However, significant damage to the brain is seen in individuals who died from paraquat intoxication, despite the fact that paraquat poorly crosses the BBB spontaneously. Furthermore, epidemiological studies have suggested an increased risk for PD due to paraquat exposure, raising the possibility that paraquat could be an environmental parkinsonian toxin. In keeping with this, it is relevant to point out that paraquat exhibits a striking structural similarity to MPTP toxic metabolite 1-methyl-4-pheylpyridinium .
What Is Tce Used For
Trichloroethylene is a halogenated hydrocarbon . These hydrocarbon compounds have at least one hydrogen atom replaced by a halogen atom, such as chlorine, fluorine, or bromine. Emil Fischer first synthesized TCE in 1864, and over the last 100 years, the chemical has had much industrial usage. Due to its age and widespread use, tce chemistry is one of the most severe environmental contaminants. New research suggests that TCE is a direct causative factor for several diseases, including liver cancer, pancreas cancer, and prostate cancer. TCE is also shown to damage fetal cardiac development and cause neurotoxicity. Trichloroethylene has also been found as a risk factor in the development of common neurodegenerative disorders such as ALS, MND, Alzheimers, and most recently Parkinsons disease.
However, there is still some variance across multiple epidemiological studies assessing TCE-related exposure and risk for developing PD. Also, there is still a degree of uncertainty about how Trichloroethylene causes toxicity to neurons, prevent neurogenesis and damage the dopaminergic system.
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What Herbicide Is Linked To Parkinsons
Parkinsons disease is caused by the loss of dopamine-releasing nerve cells in the part of the brain called substantia nigra. Dopamine helps coordinate movement in the body.
So when these nerve cells are impaired, our motor function is affected. Thats when hallmark Parkinsons disease symptoms including difficulty balancing, tremors, and slowed movement start to set in.
But aside from biological and genetic factors, research has shown that environmental exposure to toxicants such as pesticides, pollutants, and herbicides may also trigger Parkinsons disease.
In fact, aside from trichloroethylene, several environmental factors have also been associated with the development of the disease.
According to the Centers for Disease Control and Prevention , the popular herbicide known as Paraquat is a highly toxic substance which can put people at risk for severe poisoning in case of exposure.
Research has also suggested that people exposed to this herbicide may develop Parkinsons disease. In fact, the first Paraquat lawsuit back in 2017 was filed in behalf of agricultural workers and farmers who subsequently developed Parkinsons after occupational exposure to the substance.
The potentially harmful herbicide has since been banned in more than 50 countries, including China, Thailand, the United Kingdom, and other European Union nations. However, to this day, it is still widely used by farmers as a weed killer in the United States.
How Common Is Parkinsons Disease
Approximately 60,000 new cases of Parkinsons disease are diagnosed in the U.S. every year and an estimated 1.5 million people are currently living with the disease. This makes PD somewhat uncommon or even rare compared to other diseases. For example, about 130,000 cases of Alzheimers disease get diagnosed each year. Around 20,000 PD related deaths are recorded annually.
The majority of Parkinsons disease cases develop later in life. Most new cases are diagnosed after age 55. However, a certain percentage of early-onset Parkinsons disease cases occur in people in their 30s and 40s. PD is initially diagnosed based on observation of clinical symptoms and the diagnosis can be confirmed with a PET scan.
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Importance Of Parkinsons Advocacy
Not to be all doom and gloom. This is a serious issue that affects a lot of people with PD and other diseases including myself. Personally, I feel that scientific research is closing in on certain causes for developing PD and the acknowledgment by our government agencies.
I encourage you to be your own advocate. Stand up for your rights to a healthy environment and ask questions of those that include positions of influence and demand answers. Although these are two examples of recognized links to PD, I realize there are other case studies of intentional or unintentional toxic contamination of our environment. If we take action today, we can make the future better for our children and grandchildren.
One Of The First Studies To Look At Human Cells
At least 30 alterations in this gene have been associated with Parkinsons, and -synuclein protein clumps are a well-documented, albeit poorly understood, hallmark of the disease.
For the new research, the scientists also worked with normal embryonic cells that they modified using genetic editing to replicate the -synuclein genetic mutation.
Prof. Ryan explains why using human cells makes this study particularly valuable. Until now, he says, the link between pesticides and Parkinsons disease was based primarily on animal studies as well as epidemiological research that demonstrated an increased risk among farmers and others exposed to agricultural chemicals.
We are one of the first to investigate what is happening inside human cells, explains Prof. Ryan.
Stem cells are undifferentiated cells that go on to individualize into specific types of cells. Prof. Ryan and his colleagues used the two types of stem cells to derive dopamine-producing nerve cells from them.
Then, they exposed these dopaminergic neurons which are known to be affected the most by Parkinsons disease to the two pesticides.
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Do Chemicals Cause Parkinsons Disease
Short answer: The best available scientific evidence suggests that a few chemicals, including some pesticides, increase risk of Parkinsons disease, but only a small fraction of cases are believed to be caused by any sort of environmental exposure.
Longer answer: The first chemical demonstrated to cause Parkinsons disease is MPTP, as discussed here and in the fascinating book, The Case of the Frozen Addicts. MPTP, or more precisely its metabolite MPP+, is an exceptionally potent toxin that selectively kills dopaminergic neurons by poisoning their mitochondria. This is not a case of slightly increased risk it quickly and irreversibly causes symptoms essentially indistinguishable from idiopathic Parkinsons disease.
It is highly unlikely that you will come in contact with these molecules at the present time. Rather alarmingly, however, in the 1970s, MPP+ was apparently developed, and field tested, as a herbicide under the name Cyperquat, by Gulf Oil Chemicals Company .
Of much greater concern are widely used pesticides, which have been demonstrated to increase risk of Parkinsons disease with varying strengths of evidence. Some of the strongest evidence is for rotenone, thousands of tons of which have been used to kill unwanted fish and various agricultural pests it has even been used to kill head lice on humans.
Another pesticide worth highlighting is paraquat, due to its chemical similarity to MPP+.
What Are The Causes
Drug-induced parkinsonism is caused by medications that reduce dopamine levels in the brain. Dopamine is a neurotransmitter that works to control bodily movements.
Dopamine is also part of the brains reward system. It helps you feel pleasure and enjoyment, and it supports your ability to learn and focus.
Medications that bind to and block dopamine receptors are called dopamine antagonists. These medications arent used to treat Parkinsons disease. Rather, theyre used to treat other conditions that might seriously impact your quality of life.
If your doctor has prescribed a medication that causes unwanted side effects, you may have options. You may also decide that the side effects are worth it if the medication effectively treats your condition.
Some medications that cause drug-induced parkinsonism include:
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The Rise Of Parkinson’s Disease
Neurological disorders are the worlds leading cause of disability. And the fastest growing of these conditions is not Alzheimers but Parkinsons disease.
- The number of people with Parkinsons disease more than doubled from 1990 to 2015 and could double again by 2040. An aging population alone does not account for this rise.
- Air pollution, metal production, certain industrial chemicals, and some synthetic pesticides are linked to Parkinsons. Yet we are doing little to manage known risk factors.
- The authors contend that the United States should ban trichloroethylene, paraquat, and other chemicals linked to Parkinsons, which many other countries have already done.
From 1990 to 2015, the number of people living with Parkinsons more than doubled from 2.6 million to 6.3 million, according to a 2015 study in Lancet Neurology. By 2040, the number is projected to double again to at least 12.9 million, a stunning rise .
The number of people with Parkinsons disease more than doubled between 1990 and 2015 and is projected to double again by 2040.
Figure adapted from E. R. Dorsey and B. R. Bloem, 2018.
Figure adapted from R. Dorsey et al., 2020.
The number of people who succumb to Parkinsons each year has been increasing steadily.
Data from: U.S. National Center for Health Statistics, National Vital Statistics System, Mortality Data.
Christophe Vander Eecken / Reporters / Science Source
Has Anything Changed Over Time
Since most of the studies concerning PD and rural living were done decades ago, a recent study sought to revisit this issue since farming life has changed in recent times. Pesticide use is reduced, there has been a large migration from rural to urban areas, and there is less dependence on well water in rural communities.
The new study was conducted in Finland and looked at the incidence of PD in rural versus urban areas. Interestingly, rural living remained a risk factor for PD. It is possible that current diagnoses of PD continue to reflect the environmental exposures of decades ago, and that risk reduction in rural areas due to decreased pesticide use and other changes in farming life may show more benefits in the future. However, the study suggests that we may not yet fully understand how the rural environment affects Parkinsons risk.
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Researchers Think These Factors May Be Linked To Parkinsons
Dorsey and others called for a shift in current funding for biomedical research from treatment to prevention, and for further advocacy. The new policies should seek to reduce the prevalence of chemical exposure, among other goals, and mimic the efforts of smoking prevention campaigns, which have led to a steep drop in lung cancer.
If we care, we can prevent millions of people from ever developing these debilitating and deadly diseases, Dorsey said. If we educate the communities were supposed to serve, we can have them be mobilized and change the course of all these diseases.
Its a daunting task, said Walter J. Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke and co-moderator of the symposium, but I think its time to start now.
He said the institute has launched an office for exposome research, which will be conducted in close collaboration with the National Institute of Environmental Health Sciences.
These cumulative exposures are an existential threat in our modern environment, and we as neurologists and neuroscientist must focus our attention on this under-recognized and growing issue, said Frances E. Jensen, MD, president of the American Neurological Association, and chair of the symposium.
Chemical That Triggers Parkinson’s Disease Discovered
- Saint Louis University
- The key brain chemical that causes Parkinson’s disease has been discovered. This is a breakthrough finding that could pave the way for new, far more effective therapies to treat one of the most common and debilitating neurological disorders.
Researchers at the Saint Louis University School of Medicine have discovered the key brain chemical that causes Parkinson’s disease – a breakthrough finding that could pave the way for new, far more effective therapies to treat one of the most common and debilitating neurological disorders.
Currently, the main approach for treating Parkinson’s disease, which afflicts more than 1.5 million Americans, is to replace dopamine that’s lost when the cells that produce it die off and cause the disorder. With this new research, however, scientists can better work toward ‘neuroprotective’ therapies – those that actually block dopamine cells from dying off in the first place.
“We believe this work represents a very significant breakthrough in understanding the complicated chemical process that results in Parkinson’s disease,” said William J. Burke, M.D., Ph.D., professor of neurology at the Saint Louis University School of Medicine and the study’s lead author.
“For the first time, we’ve identified the chemical that triggers the events in the brain that cause this disorder,” Burke added. “We believe these findings can be used to develop therapies that can actually stop or slow this process.”
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Quality Legal Assistance For Veterans And Family Members Who Struggle With Parkinsons Disease And Were Exposed To Pfas
Since 1990, we have been helping victims of toxic exposure recover the financial compensation they deserve and are bound to provide you with quality legal assistance if you are eligible so that you can receive the money you are entitled to for your diagnosis of Parkinsons disease. If you or a family member has this diagnosis as a result of having been stationed at a military base contaminated with PFAS, our skillful team will do all in their power to obtain the compensation you are entitled to. While the legal process is quite complex, it will require minimal involvement on your part. As a veteran, you will only have to retrieve your military records and your medical records and send these documents to our experienced attorneys. If you are a veteran, your claim will also be filed with the VA so that you can receive disability compensation. Eventually, you may obtain the most favorable outcome for your case if you opt for filing your toxic exposure claim with our assistance.
Exposure To Pesticides In The Military
Agent Orange was an herbicide that US troops sprayed in Vietnam from 1961-1971 to kill trees and crops that provided protection and food to the rival army. It is a mixture of two chemicals: 2,4-Dichlorophenoxyacetic acid and 2,4,5-Trichlorophenoxyacetic acid. Agent Orange was also contaminated with Dioxin, a chemical even more damaging than Agent Orange itself, since it is very long-lasting.
The effects of Agent Orange on both the Vietnamese population and on American soldiers has been studied extensively, but with much variability in the results. Birth defects have been attributed to Agent Orange exposure, as well as multiple types of cancer.
With the understanding that the Veteran community served selflessly on behalf of the American people and therefore deserve the protection and support of the American government, the Agent Orange Act was passed in 1991, allowing the Department of Veteran Affairs to declare certain conditions presumptive to exposure to Agent Orange, even if the scientific data associating Agent Orange with that condition was not airtight.
The list of conditions has grown over the years, and in 2010, PD was added. Read here about how veterans who may have been exposed to Agent Orange and have subsequently developed PD are eligible for VA healthcare and disability compensation. APDA offers a free booklet specifically for veterans to help them find the care and support they need.
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Rural Living And An Increased Risk Of Pd
In the 1980s, studies were conducted that showed that early-age exposure to a rural environment as well as exposure to well water were associated with development of PD later in life. Subsequently, multiple additional studies looked at these questions. The studies are mixed in their conclusions, but overall the evidence supports associations between increased PD risk with each of the following:
- farming as an occupation,
- well water drinking, and
- living in a rural area.
Of course, all these categories are inter-related, since farmers live on farms in rural areas, are exposed to farm animals, are more likely than urban dwellers to drink well water and use pesticides. The studies were attempting to tease out why rural environments increased the risk of PD. Do only those who actually farm have an increased risk or is it enough to live on a farm? Is pesticide exposure the reason for the increased risk? Well water exposure? Exposure to farm animals? Or is it another element of rural life?
In the end, epidemiologic data supports the assertion that each of these elements increases the risk of PD. Of note, all of the increased risks in these studies are small on the order of 1.5-2 times the risk of the general population.
Treatment: Boosting Dopamines Effects
Your doctor might give you one of these, alone or with another drug:
- Dopamine agonists: They act like dopamine but donât raise levels of it in your brain. You can take them with any drug that has levodopa. You might try pramipexole or ropinirole .
- COMT Inhibitors: They help levodopa last longer. You might get entacapone or tolcapone .
- MAO-B inhibitors: These stop your brain from breaking down levodopa. You could get selegiline or rasagiline .
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