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Science Parkinson's

mr peabody

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Studies highlight protective effects of caffeine in Parkinson’s

Marisa Wexlerby | March 28, 2019

Two new studies in mice suggest that caffeine might have protective effects in the brains of Parkinson’s disease patients.

The studies will be presented during the 14th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders, March 26-31 in Lisbon, Portugal.

Previous epidemiological studies have suggested that consuming caffeine might protect against the development of Parkinson’s. These more-recent studies set out to test this premise more directly in an animal model.

Both studies used mouse models of Parkinson’s that involved injecting mice with alpha-synuclein. This protein is a major component of Lewy bodies, irregular “clumps” in brain cells that are a hallmark of Parkinson’s pathology. Specifically, both research teams used a mutant form of the protein called A53T, which forms these clumps even more effectively than the wild-type protein.

In both studies, injection with A53T led to changes characteristic of Parkinson’s disease, such as impaired motor function and memory, as well as changes in brain physiology, like the development of the aforementioned Lewy bodies and loss of dendritic spines (parts of neurons involved in making connections in the brain).

However, when the mice were given caffeine in their drinking water, these effects were lessened. Both studies showed similarly beneficial results, though the exact parameters that were measured were different.

In the first study, researchers at Aarhus University, Denmark, report that mice given caffeine had less alpha-synuclein in their brains. Caffeine also caused a three–week delay in the onset of clasping, which is a behavior mice do with their hind limbs that is indicative of brain damage. Furthermore, caffeine-treated mice lived, on average, 40% longer than their counterparts who weren’t given caffeine.

In the second study, researchers at Wenzhou Medical University, China, reported that mice given caffeine had fewer memory problems and more dendritic spines than their untreated counterparts.

Both studies support the previous epidemiological evidence that caffeine can be protective for Parkinson’s disease, although there is the usual caveat that experiments in animal models are never a perfect replica of actual human disease.

It also is not clear why or how caffeine might have such protective effects, and further research will be needed to figure out just how caffeine might benefit Parkinson’s patients.

https://parkinsonsnewstoday.com/2019/03/28/mouse-studies-suggest-protective-effects-of-caffeine-in-parkinsons-disease/
 
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mr peabody

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Ibogaine and neurodegenerative diseases

This is a summary on existing research into the influence of Ibogaine on glial cell line-derived neurotrophic factor (GDNF) levels in the brain, and the beneficial impact that an increase in this protein can have. While existing studies have examined these areas, few have identified a possible link between Ibogaine, GDNF expression and neurodegenerative diseases.

Both Parkinson's Disease and ALS are chronic disorders with no known cure, and require management with drugs that can have considerable side effects, causing a very poor quality of life for terminal stage sufferers of these diseases. By contrast, a low dose regime of Ibogaine or Iboga alkaloid extract would be of low toxicity and free of serious side effects.

GDNF has been shown to have potent neurotrophic factor in both rodent and primate models of Parkinson's Disease. Direct brain infusion of GDNF into the brains of five Parkinson sufferers resulted in a 39% improvement in the off-medication motor sub-score of the Unite Parkinsons Disease Rating Scale and a 61% improvement in the activities of daily living sub score. Positron emission tomography (PET) scans of dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, indicating a direct effect of GDNF on dopamine function. Furthermore, after one year, no serious clinical side effects were observed. The use of Iboga alkaloid extract or Ibogaine would provide a longer term and much less invasive method of GDNF administration than direct brain infusion. Thus, further research on Ibogaine and GDNF is certainly warranted.

Regarding motor neuron disease (ALS), the little research that has occurred in this area, such as gene transfer of neurotrophic factors, suggests potential in the treatment of motor neuron disease. Again, Ibogaine therapy may offer a straightforward, non-invasive, cheap, low-toxicity method of treatment for sufferers of this disease.


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Commonalities in the brains of people with Huntington's and Parkinson's

Boston University School of Medicine | Jan 12, 2018

A new study strongly suggests that the brains of people who have died of Huntington's disease (HD) and Parkinson's disease (PD) show a similar response to a lifetime of neurodegeneration, despite being two very distinct diseases. The study found that most of the genes perturbed in brains from both diseases are related to the same immune response and inflammatory pathways. Inflammation in the central nervous system has recently been shown to play a role in a number of different neurodegenerative diseases, including HD and PD, but this is the first direct comparison of these two distinct diseases.

Brains of persons who died with Huntington's, Parkinson's or no neurological condition were analyzed using sequencing technology that provides a data readout of the activity of all genes in the genome. By comparing the data from the different groups, the researchers identified which genes show differences in their activity. By organizing and interpreting these genes, the researchers found an overall pattern of commonality between the two diseases. According to the researchers, the hypothesis that the brain experiences a similar response to disparate neurodegenerative diseases has exciting clinical implications.

"These findings suggest that a common therapy might be developed to help mitigate the effects of different neurodegenerative diseases of the central nervous system"
explains author Dr. Adam Labadorf. "Though no such treatment yet exists, this finding will lead to experiments to better understand the specific mechanisms of the inflammatory response in the neurodegenerating brain, which may in turn lead to new treatments."

Labadorf believes that at present, these findings are too preliminary to suggest new clinical treatments. However, as many anti-inflammatory drugs are already available, there may be a relatively short path to designing clinical trials for drugs that modulate the inflammatory response in people with neurodegenerative disease.

"While these findings are specific to HD and PD, these two diseases are sufficiently distinct to suggest that the observed pattern of differential gene activity may likely be observed in other neurodegenerative diseases of the central nervous system, including Alzheimer's disease and Chronic Traumatic Encephalophathy (CTE)."

 
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Can the flu and other viruses cause neurodegeneration?

by Ashley Yeager | Mar 1, 2019

Scientists may need to seriously reconsider the cast-aside hypothesis that pathogens don't play a part in diseases such as Alzheimer’s and Parkinson’s.

little more than 10 years ago, when neurobiologist Richard Smeyne was working at St. Jude Children’s Research Hospital in Memphis, he saw a video of a duck acting strangely. The white-feathered, orange-billed bird was standing slightly apart from its flock on a farm in Laos. It walked in circles and flipped up a wing, then lost its balance and fell over. It got up, tried to flap both wings, and fell over again.

Smeyne saw the video while attending a seminar being given by then-postdoc David Boltz and Boltz’s advisor, a “flu hunter” named Robert Webster, who headed the influenza research program at the hospital. The duck, Boltz and Webster explained, was infected with the H5N1 bird flu virus that had sickened thousands of birds and killed hundreds of people in 2006 and 2007. Smeyne, who had been studying the neurobiology of Parkinson’s disease in mice, recognized the animal’s motor issues. That duck has Parkinson’s, he thought.

He told Webster this after the seminar, and Webster laughed, Smeyne recalls. “He said, ‘Well, it’s a sick bird.’” But Smeyne was curious about the neural mechanisms underlying the duck’s abnormal behavior. He wondered if healthy ducks infected with H5N1 in the lab would show Parkinson’s-like neurodegeneration. In St. Jude’s biosafety level 3 lab, he and his colleagues infected ducks with the virus, then sacrificed the birds and removed their brains, storing them in formaldehyde for three weeks to kill the active virus.

When Smeyne began to dissect the once-infected duck brains, he focused on a region called the substantia nigra, which is often damaged in Parkinson’s patients. “When I opened it up, when I cut the brain, the substantia nigra was devastated. All the neurons were completely gone,” Smeyne says. He went back to Webster, he recalls, and said, “I wasn’t wrong. Your duck does have Parkinson’s disease.”

Because the bird had had the flu, Smeyne wondered whether there was a connection between the viral infection and the extensive neurodegeneration he observed. He asked Webster about the symptoms experienced by people infected with H5N1. Webster’s answer—inflammation of the brain that leads to tremors and other motor malfunctions—didn’t sound like “full-blown Parkinson’s disease,” Smeyne says, “but it was parkinsonism,” a subset of symptoms of the disease.

Looking into the literature, Smeyne found more hints of influenza’s ability to damage the brain. One of the earliest links between influenza and neural dysfunction was a correlation between the 1918 Spanish flu, caused by a subtype called H1N1, and an epidemic of Parkinson’s a few decades later. In the 1940s and early 1950s, diagnoses of the neurodegenerative disease appeared to increase abruptly, from 1–2 percent of the US population to 2.5–3 percent, then fell back down to 1–2 percent, Smeyne says. “Basically, 50 percent more people in those years got Parkinson’s.”

The evidence to suggest that influenza infection caused the neurodegenerative disorder was tenuous, to say the least, but the correlation was enough for Smeyne to investigate further. With his colleagues, he shot nonlethal doses of H5N1 or H1N1 up the noses of six- to eight-week-old mice, then tracked how the viruses spread through the animals’ nervous systems. The results were startling, he says: some viruses weren’t blocked from entering the brain by the blood-brain barrier—a semipermeable layer of cells that separates the central nervous system from the body’s circulation. H5N1, for example, could easily infiltrate nerve cells in the brain and kill them, and it appeared to especially target the dopamine-producing neurons in the substantia nigra. And while the H1N1 flu strain couldn’t cross the blood-brain barrier, it still caused central nervous system immune cells called microglia to flow into the substantia nigra and the hippocampus, causing inflammation and cell death in the area.

“So these were two different flus, two different mechanisms, but the same effect in a sense,” says Smeyne, who moved to Thomas Jefferson University in Philadelphia in 2016. “They were inducing inflammation and death in the parts of the brain that we see degenerate in Parkinson’s disease.”

Smeyne’s experiments aren’t the only ones to suggest that viral infections can contribute to neurodegenerative disorders, and the connection is not limited to influenza. Several different viruses, including measles and herpes, can give rise to symptoms of multiple sclerosis (MS) in rodents, for example. And levels of herpesvirus are higher in the brains of people who died from Alzheimer’s than in those without the disease,4 while some HIV patients develop dementia that appears to be associated with the infection.

“Viruses are often ignored in relation to neurodegenerative diseases,” Yale University neurobiologist Anthony van den Pol tells The Scientist. “That’s in part because there’s no clear sign that a virus causes a neurodegenerative disease. But it might.”

Invading the brain

As far back as 1385, doctors in Europe recorded connections between influenza infection and psychosis. That link between the flu and the brain became much more apparent during and after the 1918 Spanish flu epidemic. More direct evidence for the virus-brain link came in the 1970s, when researchers led by Eugenia Gamboa, then a neurologist at Columbia University, and colleagues found viral antigens in the brains of deceased people who had been afflicted with a condition known as encephalitis lethargica. Having symptoms such as fever, headache, and double vision, encephalitis lethargica was associated with—and, some thought, caused by—the 1918 Spanish flu, and researchers speculated that the condition could be a precursor to Parkinson’s symptoms. Then, in 1997, a team of scientists reported that rats exposed to Japanese encephalitis virus developed a disease with symptoms similar to human Parkinson’s disease.

But the connection between viral infection and brain disease has been hotly contested. And when researchers from the Armed Forces Institute of Pathology in Washington, DC, used PCR to look for fragments of the H1N1 genome in the preserved brain tissue of victims of encephalitis lethargica in the early 2000s, they found no signs of the virus.

Such was the state of research when Smeyne uncovered the severe Parkinson’s-like brain damage in the H5N1-infected ducks. No one had directly tested the virus’s ability to cause Parkinson’s disease until he infected mice with H5N1 and documented severe damage to the substantia nigra. His results also revealed a possible pathway for the virus to spread from the body into the brain. "The substantia nigra," Smeyne says, "wasn’t the virus’s initial target; it infected neurons in the gut first. Then, the virus went into the vagus nerve and basically used the vagus nerve as a back door into the brain.”

Routes of passage

Some viruses can enter the body through the nose and mouth and move to the brain by replicating and spreading through the olfactory bulbs; the lingual nerve, which runs down the jawline and into the tongue; or the vagus nerve, which travels through the neck and thorax to the stomach.

The pattern is strikingly similar to how Parkinson’s disease appears to work its way through the human body, Smeyne says. According to a widely accepted hypothesis first proposed by German neuropathologist Heiko Braak in 2003, Parkinson’s disease starts in the gut, manifesting as digestive issues, and then moves into the brain. “The progression of the disease from the gut to the forebrain, that takes place over maybe 25 or 30 years in a human,” Smeyne says. But mice live much shorter lives. "In the rodents, the flu virus can travel the same course and create signs of Parkinson’s in a few weeks," he notes. And as Smeyne and his colleagues found with H1N1-infected mice, viruses unable to make it into the brain can still play a part in neurodegeneration, by triggering severe inflammation.

Some research has failed to find a link between viral infection and damage to the brain, however. For example, when researchers at the US Centers for Disease Control and Prevention in Atlanta, Georgia, studied the effects of the influenza strain that caused the 1918 Spanish flu epidemic, they didn’t see any signs of inflammation in the brains of infected mice. “More work is needed to look for a link between viral infection and neurodegenerative diseases,” says microbiologist Terrence Tumpey, who coauthored that study.

Smeyne suspects the link between viruses and brain-centered diseases could be more subtle. To further explore the relationship between H1N1 and Parkinson’s, he and his colleagues gave a toxin called MPTP to mice that had recovered from infection with the virus. The chemical was a byproduct of a bad batch of synthetic heroin cooked up in the 1970s that led users to develop Parkinson’s disease. The MPTP-treated mice that had been infected with H1N1 developed signs of the disease and lost 25 percent more neurons in the substantia nigra than uninfected mice treated with the toxin or mice infected with the virus but not exposed to MPTP.

“That suggested to us,” Smeyne says, “that while the H1N1 infection alone did not cause Parkinson’s, it primed the nervous system to be sensitive to other things that would.”

A broader link between viruses and neurodegeneration

The flu-Parkinson’s connection is not the only link researchers have made between viruses and neurological problems. In the late 1980s and early 1990s, researchers found that mice infected with viruses such as measles and herpes suffered the same kind of damage to their oligodendrocytes—cells in the central nervous system that produce myelin, the insulating fatty sheath wrapped around the axons of neurons—as patients with MS do. "It’s not clear whether the viruses invaded the oligodendrocytes directly, or simply provoked the mice’s immune systems to attack the cells, but the end result was demyelination of neurons," van den Pol says, "just like what is seen in MS patients."

Smoother neurons

Tiny bumps called dendritic spines are important structures for neuronal communication, receiving messages from other nerve cells in the brain. Mice infected with H3N2 and H7N7 experienced a drop in the number of these bumps, researchers recently showed. The number of bumps did not decrease following infection with H1N1.

One of the virus strains that induced MS symptoms in mice was herpesvirus 6, which has also been associated with the development of Alzheimer’s disease. Tentative links between viral infections and Alzheimer’s have been documented over the past few decades, but the possibility reemerged last year when Joel Dudley of the Icahn School of Medicine at Mount Sinai and colleagues, reviewing data from brain banks and published studies, found that patients with Alzheimer’s disease had elevated levels of viruses, such as human herpesvirus 6 and human herpesvirus 7, in four key brain regions. Based on genetic and proteomic data, the researchers also found that human herpesvirus 6 may induce gene expression that spurs the development of the protein amyloid β, which forms plaques that are hallmarks of Alzheimer’s disease.

"Such a correlation doesn’t prove that viruses cause the disease, but it does suggest that pathogens may play a part in neurodegenerative diseases after all," Dudley says. “One thing that’s different today compared to previous musings on the pathogen hypothesis is that we have much more powerful sequencing methods that can take a more unbiased look at the microbial DNA/RNA landscape of brain tissue,” he says. “We are likely to get an even better look at this question as we apply long-read sequencing technology and single-cell sequencing technology to brain tissue samples.”

HIV is another virus researchers suspect could cause Alzheimer’s-like or Parkinson’s-like brain damage. In the 1990s, scientists showed that HIV could traverse the blood-brain barrier, and subsequent studies revealed that when the virus infiltrates the brain, it spurs neuronal death and a loss of synaptic connections. "More recently, physicians have started reporting on patients with HIV who develop dementia and a loss of brain matter that mirrors what’s seen in Alzheimer’s patients," Sara Salinas, a pathologist and virologist at the University of Montpellier in France, and colleagues explain in a 2018 review article in Frontiers in Cellular Neuroscience. More-recent studies show that HIV patients develop plaques of amyloid β. "And," Smeyne says ,"HIV patients can also develop slowness in movement and tremors."

Crossing blood-brain barrier

When interacting with the nervous system, viral particles can cross the blood-brain barrier directly or through infection of endothelial cells (below, left), or they can use a Trojan horse approach (center), infecting monocytes that cross the barrier before replicating and bursting out of the white blood cells once inside the brain. Alternatively, some viruses do not cross the blood-brain barrier but invoke an immune response that may spur cytokines or chemokines to breach the divide (right).

A closer look at modes of neuronal communication may give some clues to the development of the neurodegenerative diseases. Earlier this year, two groups of scientists reported that, in addition to using electrical and chemical signals to talk to one another, neurons employ extracellular vesicles carrying messenger RNAs. "The structure of these vesicles is reminiscent of the way HIV and other retroviruses build protective shells called capsids that ferry the virus’s genetic material from cell to cell," says Jason Shepherd, a neuroscientist at the University of Utah and coauthor of one of the studies. The genes encoding the vesicles could possibly be holdovers from past infections, he suggests, and these virus-mimicking capsids could be harboring toxic proteins, such as amyloid β, and spreading them throughout the brain.

“Clearly, viruses influence the brain,” Shepherd says, but the nature of that relationship remains unclear.

Brain damage

Once inside the brain, viruses can infect cells or their myelin sheaths and kill them (below, left). Viruses don’t necessarily have to enter the brain to cause damage, though. They can also spark an immune response that activates microglia, which then consume otherwise healthy neurons (right).

Forgetfulness lingers

One challenge in understanding how the brain responds to viral infection is that the effects can linger long after our immune system has cleared the infection from our bodies. Earlier this year, for example, Martin Korte at the Technische Universität Braunschweig in Germany and colleagues reported that the brains of mice infected with certain strains of the flu virus suffered memory deficits even after they’d seemingly recovered. It turned out that their brains were full of microglia even 30 to 60 days after infection first took hold. The microglia levels can start to return to the normal range around 60 days post infection, with the neurons in the young mice recovering completely, along with the animals’ memory performance. Still, the microglia numbers can stay elevated for up to 120 days, Korte tells The Scientist; that’s equivalent to more than 10 years in human time.

Van den Pol says such a lag is exactly why scientists have trouble accepting that viruses could cause neurodegenerative diseases. “In science we often think of some cause and effect being often milliseconds,” he says. “Here, you’re talking about decades. The virus goes in and then maybe decades later it can cause some potentially serious neurodegeneration”—such a long-term link is hard to demonstrate.

"If the connection between viral infections and neurological problems can be more concretely established, researchers may be able to develop ways to mitigate the neurological effects," van den Pol says. "Understanding how infections trigger the immune system, for example, could lead to ways to downregulate glia-driven inflammation in hopes of preventing long-term damage," he suggests.

In the meantime, Smeyne notes that vaccination for the flu—or at the very least, taking Tamiflu if a person gets infected—might help prevent neurological complications of influenza infection. He and his colleagues tested this approach in mice after their results revealed the link between flu, the MPTP toxin, and Parkinson’s disease. The team gave a group of mice an H1N1 vaccine 30 days before infecting the animals with the virus. Another group of mice were treated with Tamiflu for the week after they were infected. Both groups of mice were allowed to recover before being given a low dose of MPTP. While control mice that did not receive either the vaccine or flu treatment developed Parkinson’s-like symptoms, treated mice developed no neurodegenerative effects. “We had protected against [Parkinson’s-like symptoms] just by early treatment or prophylactic treatment with the vaccine,” Smeyne says.

"It’s further evidence to support the idea that viral infections can damage the brain," Smeyne says, "but there’s still no slam-dunk study that demonstrates a virus can cause Parkinson’s, or Alzheimer’s, or any number of other neurological disorders. I do like the idea that viruses can cause a lot of different brain diseases as a hypothesis,” van den Pol says. “But I also respect the fact that it really is a hypothesis.”

 
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mr peabody

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Vitamin B12 found to inhibit a key enzyme in hereditary Parkinson’s disease

Neuroscience News | April 4, 2019

Vitamin B12 significantly prevents the neurotoxicity of LRRK2 genetic variants associated with hereditary Parkinson’s disease. The findings may help with the development of new therapies to combat the neurodegenerative disease.

Parkinson’s is the most common, chronic neurodegenerative movement disorder affecting 1% of the global population over seventy years of age. Right now, there is no cure for this disease and the available treatments focus on addressing its symptoms but not its progression.

Although most cases of Parkinson’s are sporadic, the inheritable variants of the disease are mainly associated with mutations of the gene that encodes the LRRK2 enzyme. In 2004 an international research team, in which researchers from the Basque Country participated, established the link between one of the mutations in this enzyme and patients diagnosed with the disease.

So the LRRK2 enzyme, which is also known internationally by the name “dardarina”, the Basque word that means tremor, has become one of the most attractive therapeutic targets for developing new drugs to combat inheritable Parkinson’s. Neurotoxicity, or the pathogenic effects as a whole associated with LRRK2, is mainly due to the fact that pathogenic mutations increase the kinase activity of this enzyme, which has prompted an international race to develop inhibitors. Right now, specific, powerful inhibitors of the kinase activity of LRRK2 do in fact exist. Yet many of them cause undesirable side effects or produce very unclear clinical results.

This research conducted by Iban Ubarretxena, the Ikerbasque researcher and director of the Biofisika Institute (mixed centre of the CSIC-Spanish National Research Council and the UPV/EHU-University of the Basque Country) at the UPV/EHU’s Science Park (Leioa-Erandio Area), together with an international research team, has revealed that AdoCbl, one of the active forms of vitamin B12, acts as an inhibitor of the kinase activity of LRRK2 in cultured cells and brain tissue. It also significantly prevents the neurotoxicity of the LRRK2 variants associated with Parkinson’s in cultured cells of primary rodents, as well as in various genetically modified models used to study this disease. The results of the research have been published in the prestigious journal Cell Research.

So according to the study, vitamin B12 has turned out to be a new class of modulator of the kinase activity of LRRK2, which, as Iban Ubarretxena pointed out, “constitutes a huge step forward because it is a neuroprotective vitamin in animal models and has a mechanism unlike that of currently existing inhibitors. So it could be used as a basis to develop new therapies to combat hereditary Parkinson’s associated with pathogenic variants of the LRRK2 enzyme”.

 
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The research has presented strong evidence that Parkinson’s disease
begins in the gastrointestinal tract, and spreads via the vagus nerve
to the brain. Many patients have also suffered from gastrointestinal
symptoms before the Parkinson’s diagnosis is made.



Parkinson’s may begin in gut and spread to the brain via the vagus nerve*

NEUROSCIENCE NEWS

A major epidemiological registry-based study from Aarhus University and Aarhus University Hospital indicates that Parkinson’s disease begins in the gastrointestinal tract; the study is the largest in the field so far.

The chronic neurodegenerative Parkinson’s disease affects an increasing number of people. However, scientists still do not know why some people develop Parkinson’s. Now researchers from Aarhus University and Aarhus University Hospital have taken an important step towards a better understanding of the disease.

New research indicates that Parkinson’s disease may begin in the gastrointestinal tract and spread through the vagus nerve to the brain.

“We have conducted a registry study of almost 15,000 patients who have had the vagus nerve in their stomach severed. Between approximately 1970-1995 this procedure was a very common method of ulcer treatment. If it really is correct that Parkinson’s starts in the gut and spreads through the vagus nerve, then these vagotomy patients should naturally be protected against developing Parkinson’s disease,” explains postdoc at Aarhus University Elisabeth Svensson on the hypothesis behind the study.

A hypothesis that turned out to be correct

“Our study shows that patients who have had the the entire vagus nerve severed were protected against Parkinson’s disease. Their risk was halved after 20 years. However, patients who had only had a small part of the vagus nerve severed where not protected. This also fits the hypothesis that the disease process is strongly dependent on a fully or partially intact vagus nerve to be able to reach and affect the brain,” she says.

The research project has just been published in the internationally recognised journal Annals of Neurology.

The first clinical examination

The research has presented strong evidence that Parkinson’s disease begins in the gastrointestinal tract and spreads via the vagus nerve to the brain. Many patients have also suffered from gastrointestinal symptoms before the Parkinson’s diagnosis is made.

“Patients with Parkinson’s are often constipated many years before they receive the diagnosis, which may be an early marker of the link between neurologic and gastroenterologic pathology related to the vagus nerve ,” says Elisabeth Svensson.

Previous hypotheses about the relationship between Parkinson’s and the vagus nerve have led to animal studies and cell studies in the field. However, the current study is the first and largest epidemiological study in humans.

The research project is an important piece of the puzzle in terms of the causes of the disease. In the future the researchers expect to be able to use the new knowledge to identify risk factors for Parkinson’s disease and thus prevent the disease.

“Now that we have found an association between the vagus nerve and the development of Parkinson’s disease, it is important to carry out research into the factors that may trigger this neurological degeneration, so that we can prevent the development of the disease. To be able to do this will naturally be a major breakthrough,” says Elisabeth Svensson.

 
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Radical Parkinson's treatment tested in patients

by Alex Therrien | 27 February 2019

A radical Parkinson's treatment that delivers a drug directly to the brain has been tested in people.

Patients in the trial were either given the drug, which is administered via a "port" in the side of the head, or a dummy treatment (placebo).

Both groups showed improved symptoms, meaning it was not clear if the drug was responsible for the benefits.

However, scans did find visual evidence of improvements to affected areas of the brain in those given the drug.

The study's authors say it hints at the possibility of "reawakening" brain cells damaged by the condition.

Other experts, though, say it is too early to know whether this finding might result in improvements in Parkinson's symptoms.

Researchers believe the port implant could also be used to administer chemotherapy to those with brain tumours or to test new drugs for Alzheimer's and stroke patients.

Parkinson's causes parts of the brain to become progressively damaged, resulting in a range of symptoms, such as involuntary shaking and stiff, inflexible muscles.

About 145,000 people in the UK have been diagnosed with the degenerative condition, which cannot be slowed down or reversed.

For this new study, scientists gave patients an experimental treatment called glial cell line-derived neurotrophic factor (GDNF), in the hope it could regenerate dying brain cells and even reverse the condition.

Participants underwent robot-assisted surgery to have four tubes placed into their brains, which allowed GDNF to be infused directly to the affected areas with pinpoint accuracy, via a port in their head.

After an initial safety study of six people, 35 patients took part in a nine-month "blinded" trial, where half were randomly assigned to receive monthly infusions of GDNF and the other half dummy infusions.

Dr Alan Whone, principal investigator, said patients in the trial had, on average, been diagnosed eight years previously, but brain scans of those given the drug showed images that would be expected just two years after diagnosis.

"We've shown with the PET [positron emission tomography] scans that, having arrived, the drug then engages with its target, dopamine nerve endings, and appears to help damaged cells regenerate or have a biological response," he said.

Tom Phipps, 63, from Bristol, said he had noticed an improvement during the trial and had been able to reduce the drugs he takes for his condition.

Since it ended, he has slowly increased his medication but is continuing to ride his bike, dig his allotment and chair his local branch of Parkinson's UK.

"My outcome was as positive as I could have wished for," he said. "I feel the trial brought me some time and has delayed the progress of my condition. The best part was absolutely being part of a group of people who've got a similar goal - not only the team of consultants and nurses but also the participants. You can't have expectations - you can only have hope."

Following the initial nine months on GDNF or placebo, all participants had the opportunity to receive GDNF for a further nine months.

By 18 months, when all participants had received GDNF, both groups showed moderate to large improvements in symptoms compared with their scores before they started the study.

https://www.bbc.com/news/health-47370498
 
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Neurosurgery in Parkinson's


New method developed to target the cause of Parkinson’s

Neuroscience News | May 3, 2019

Researchers from Oxford’s Department of Physiology, Anatomy and Genetics (DPAG) have identified how the dysfunction of a key protein, LRRK2, causes the neurons affected in Parkinson’s to lose their ability to effectively clear out cell components that have been damaged. This discovery has enabled the team to find a new way to target and correct this issue, paving the way for a potential new clinical treatment.

Parkinson’s is a motor disorder caused by the loss of a specific sub-set of neurons located in the midbrain. Although the underlying mechanisms leading to the death of these neurons is still not well understood, one of the leading theories is that they die as they accumulate protein aggregates.

Evidence from recent years points to lysosomes, the cellular organelle in neurons responsible for clearing out waste, as a leading culprit for the progression of Parkinson’s. The lysosomes do not work well enough in those with the condition, which causes damaged cell components to build up and clump together.

About 10% of Parkinson’s is genetic, and lysosomes are implicated in the progression of both the inherited condition and in those with no family history of disease. Mutations in the gene LRRK2 are the most common genetic cause of Parkinson’s, and these mutations have been heavily implicated in causing the lysosomes to stop working properly. However, researchers have been trying to ascertain exactly what LRRK2 does for some time and the mechanism by which LRRK2 regulates lysosomal function is still not clear.

In a new study, the Wade-Martins Group has identified for the first time both an important role of LRRK2 and a new way to target its dysfunction therapeutically. Lysosomes need to be acidic to work properly and effectively degrade the waste proteins, and the team’s research demonstrates that LRRK2 regulates the way that lysosomes are acidic. In Parkinson’s, the mutated LRRK2 is not able to perform this function, so lysosomes lose their acidity as a result of LRRK2 dysfunction.

They also found that a drug called clioquinol, currently used as an anti-parasitic drug, overcomes the effect of the mutant LRRK2 and restores the acidity of the lysosome and clears out the protein aggregates. Consequently, the team was able to restore the ability of the lysosomes to “chew up this pathological protein burden” (Prof Wade-Martins) and clear out the protein aggregates that are killing the neurons.

Evidence from recent years points to lysosomes, the cellular organelle in neurons responsible for clearing out waste, as a leading culprit for the progression of Parkinson’s. The lysosomes do not work well enough in those with the condition, which causes damaged cell components to build up and clump together.

This data identifies a novel mechanism of LRRK2 mutations and ultimately demonstrates the importance of LRRK2 in lysosomal biology, as well as the critical role of the lysosome in Parkinson’s.

Professor Richard Wade-Martins of Oxford’s Department of Physiology, Anatomy and Genetics (DPAG), said: ‘As the population in the United Kingdom gets older, we’re all ageing, the incidence of Parkinson’s is going to increase. We urgently need a better understanding of what causes the disease and then apply that knowledge to develop new therapies, and that is what our work has done. Our work identifies for the first time the very important role of LRRK2 in regulating the acidity and the normal function of the protein recycling centre, the lysosome, and identifies a new way to target this therapeutically in Parkinson’s.’

The successful use of clioquinol to reverse the effects of this mutation highlights the potential of drugs targeting the lysosome in future therapeutics of not only Parkinson’s, but also other neurodegenerative diseases where lysosome dysfunction has been implicated.

 
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Italian doctor quells Parkinson’s with overlooked vitamin cure

by Bill Sardi | Health Freedom News® | 28 December 2016

In recent weeks the World has learned the news media creates fake news and/or completely shuns significant news stories to match its own politically correct agendas. So an unequivocal cure for a major brain disease goes unreported. Shame on CNN,CBS, ABC, NBC, the BBC, Reuters, Associated Press,Washington Post, and the New York Times. For a disease considered incurable, a physician in Italy has begun to provide a common B vitamin to successfully treat a debilitating motor-nerve disease commonly known as Parkinson’s disease. The importance of this startling discovery has escaped major news outlets. It should be heralded on television and in newspapers worldwide. But it has only been reported by an obscure European news source.

History of vitamin B1 and Parkinson’s

In 1817, physician James Parkinson first described a “shaking palsy.” Today, 200 years later, Parkinson’s disease is still considered an incurable disease.Parkinson’s disease emanates from the loss of dopamine-producing cells in the brain. Approximately 60-80% of dopamine-producing cells are damaged before symptoms arise. Dopamine is a nerve-transmitting chemical in the brain.It has taken two centuries for a vitamin-phobic medical profession to hesitantly begin to treat Parkinson’s disease with Vitamin B1 (thiamin). Historically, the link between Parkinson’s disease and thiamin deficiency has been agonizingly slow to develop. Thiamin, or Vitamin B1, was the first vitamin to be discovered. Vitamin B1 was first synthesized in 1936. So, dietary supplementation was possible from that point forward.

It took until 1967 for the first published report to appear showing that a decline in brain dopamine levels of pigeons was due to experimentally induced thiamin deficiency. A link between thiamin deficiency and low dopamine levels was discussed in 1987 in an experiment that attempted to determine why rats tend to eat mice (muricide). Low dopamine levels induced by a shortage of thiamin in the diet were linked to this abnormal animal behavior.

In 1988, researchers noted a thiamin-deficient diet decreased dopamine concentrationand synthesis in the brain (striatum). The provision of alcohol to lab animals also decreased dopamine levels. The brain region most susceptible to damage (the hypothalamus) in thiamin-deficient animals is the very same region of the brain that produces dopamine. In 1999, it was observed that low levels of thiamin in the cerebrospinal fluid were related to Parkinson’s disease. In 2013, researchers reviewed all prior, published scientific reports and concluded that thiamin plays a role in Parkinson’s disease.

First therapeutic trials report

In 2013, the first reportswere published demonstrating the use of high-dose thiamin among Parkinson’s disease sufferers resulted in considerable improvement in measured motor function (31 to 77 percent). Injection of high-dose thiamin was effective in reversing symptoms. Then, another study published in 2015 confirmed that injectable thiamin treatment (100 mg twice a week) improves motor-nerve function among Parkinson’s patients. In 2016, researchers in Italy reported on the successful use of high-dose thiamin among Parkinson’s patients. Notably, all of the patients had normal blood levels of thiamin, yet thiamin therapy led to significant improvement in Parkinson’s symptoms. There were no adverse effects.

Loss of sense of smell is earliest sign

Finally, in January of 2017, researchers noted that the sense of smell declines years prior to the onset of Parkinson’s disease. Scented strips were used to test scent among individuals with Parkinson’s disease. Almost half of the individuals tested (47 percent) scored low on this test and dietary thiamin was also low in these subjects.The main finding of the study was an association between low thiamin in the diet reported 2-8 years prior to the onset of symptoms and diagnosis. Impairment of olfaction (sense of smell) is a characteristic and early feature of Parkinson’s disease, these researchers wrote. Involvement of many B-family vitamins appears to be involved in the decline of smell. Therefore, a decline in the sense of smell may serve as an early screening tool for Parkinson’s disease.

Because of a change in Western diets, Dr. Derrick Lonsdale, the reigning clinical authority on Vitamin B1, says the high sugar/carbohydrate diet of today results in a return of the scourge of beri beri. The problem is, modern medicine observes symptoms of this nutrient deficiency disease and treats those instead of its cause.Western populations are paying a high price for poor absorption or depletion of thiamin due to consumption of alcohol, drugs like diuretics (water pills), refined sugar, carbohydrates, and even coffee and tea. The ordeal of undetected thiamin deficiency is only exacerbated by the modern paradigm of treating symptoms of disease as if they emanate from the drug deficiency, not a nutrient deficiency.

So, we now have 60,000 Americans diagnosed with Parkinson’s disease annually and 10 million worldwide living with the disease. More than 23,000 individuals die of Parkinson’s disease annually in the U.S. And Levodopa, the main drug prescribed for Parkinson’s disease, costs approximately $2500 per year. As of 2014, there were 23 medicines under development for Parkinson’s disease. Drugs only serve as a distraction for a disease that may emanate from a vitamin deficiency.

Rx: B Vitamins

The provision of the entire family of supplemental B vitamins, in particular thiamin (B1), pyridoxine (B6), folic acid(B9), and cobalamin (B12) appears to be important in the theoretical model of these diseases. Disturbed sense of smell has been reversed with Vitamin-B12 supplementation. The best way to achieve this proposed prophylaxis is either with a B-vitamin complex or a multivitamin. Unfortunately, in most instances the provision of B vitamins in these formulas is marginal, often not exceeding the outdated Daily Value or the Recommended Daily Allowance.

A progressive fall-off in the absorption of these B vitamins due to a decline in secretion of stomach acid with advancing age, or in the case of thiamin the blockage of absorption by drugs, antacids, alcohol, sugar and carbohydrates and even presumably healthy beverages like tea and coffee, serve as sufficient evidence that doses of B vitamins need to be updated in most multivitamins if a universal attempt is to be made to head off Parkinson’s and Alzheimer’s disease epidemic.

Because of poor absorption of water-soluble forms of B1, Vitamin B1 in fat-soluble form (Benfotiamine) is the preferred form in dietary supplements but is generally not providedin B-complex or multivitamins. Fat-soluble benfotiamine is almost six times more biologically available than water-soluble thiamin hydrochloride, the common form used in dietary supplements.

Furthermore, gut bacteria has now been shown to regulate movement disorders like Parkinson’s disease in laboratory mice and represents a risk factor. Multivitamins need to incorporate ingredients that promote healthy gut bacteria. As for the doctor in Italy who has reported on the successful use of thiamin/Vitamin B1 for Parkinson’s disease symptoms, we can only say Bravo, and wonder when the Nobel Prize committee will take notice.


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Stop progression, suppress motor and non-motor symptoms

My name is Marco Colangeli, I am Dr. Costantini's research assistant, and co-author. Thank you very much for opportunity to share the findings of our research with more patients.

From our point of view there are a few aspects that should be highlighted and possibly further mainstreamed:

1) It is important from our point of view that also your own practitioners and MD are involved with this novel therapy. Therefore we do call upon your contribution to this research by informing your Doctors about this therapy and the beneficial effects you are experiencing. We have experienced an unspeakable amount of skepticism and lack of trust towards this simple yet incredibly effective therapy. If on the one hand we can see why this may happen, on the other hand we do consider that regardless the personal skepticism or any less-than-professional form of competition among doctors, it is fundamental for the well-being of the patients that your doctors are asked to contribute actively. This is particularly relevant in light of the fact that we have limited time and resources to follow a continuously increasing number of patients worldwide.

2) It is paramount that out clinical findings are taken to the next level by partnering with research institutes and pharmaceutical companies to fully understand and fully exploit the potential of this therapy. Our resources are too limited (since 2011 we have worked on this 100% without any form of external funding sometimes even purchasing from third parties the thiamine to provide our patients with) and we cannot mainstream the results of this research alone. The exact mechanisms of action of Thiamine on PD patients (as well as on a number of other conditions we have studied and documented at case-study level) must be researched and fully comprehended. Moreover, in the context of a proper double blind label type of research, this therapy can be A) improved even further and B) recognized by the scientific community. The most direct consequence of this is that millions of patients worldwide will experience the same if not better results that those who have tried the therapy because already in direct contact with us have.

 
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mr peabody

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Iboagine and Parkinson's

by Hamilton Morris

One of the most interesting things that I have researched regarding ibogaine is its effect on a protein called GDNF – that’s Glial Cell Derived Neurotrophic Factor. And this is a protein that is very useful in the treatment of Parkinson’s disease. There’s been some limited clinical work where they showed that it can cause a regrowth of dopaminergic neurons, which is the mechanism of Parkinson’s. Damage to the brain is loss of dopaminergic neurons. So it’s directly reversing the toxic effect of Parkinson’s. And they found that ibogaine causes a release of the same therapeutic protein. So that’s pretty damn useful. And that’s just the tip of the iceberg with it. It also seems to synergize with dopaminergic drugs. So it’s possible that it increases patient sensitivity to the L-dopa treatment as well.

And on top of that, it seems to have an antidepressant effect, and depression is one of the major symptoms of Parkinson’s disease. So I think it could really be helping people with Parkinson’s. And there’s a sort of underground community of people with Parkinson’s that use ibogaine. And I occasionally receive emails from these people. Often they use it at 20 mg a day, and they seem to really believe in it as a treatment. On one hand, I understand that it’s irresponsible to talk about these things without a lot of serious medical support, but the flipside is that it needs to be studied. People need to be aware of it. There is no treatment available that’s actually addressing the root cause of the neurodegeneration. And if patients are being deprived that treatment, that’s a tragic thing.
 
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Bipolar disorder may be linked to Parkinson’s

Neuroscience News | May 23, 2019

People with bipolar disorder have higher incidences of Parkinson’s disease than those without the psychiatric condition. Manic and depressive episodes were associated with an elevated risk of developing Parkinson’s disease.

People who have bipolar disorder may be more likely to later develop Parkinson’s disease than people who do not have bipolar disorder, according at a study published in the May 22, 2019, online issue of Neurology.

“Previous studies have shown a relationship between depression and Parkinson’s disease, but few studies have looked at whether there is a relationship between bipolar disorder and Parkinson’s,” said study author Mu-Hong Chen, MD, PhD, of Taipei Veterans General Hospital in Taiwan.

For the study, researchers examined a national Taiwanese health database for people were diagnosed with bipolar disorder between 2001 and 2009 and who had no history of Parkinson’s disease, for a total of 56,340 people. They were matched with 225,360 people of the same age, sex and other factors who had never been diagnosed with bipolar disorder or Parkinson’s disease as a control group. Then the two groups were followed until the end of 2011.

During the study, 372 of the people with bipolar disorder developed Parkinson’s disease, or 0.7 percent, compared to 222 of those who did not have bipolar disorder, or 0.1 percent.

After adjusting for other factors that could affect the risk of developing Parkinson’s disease, such as age, sex, use of anti-psychotic medications, and medical issues such as traumatic brain injury and cerebrovascular diseases, people with bipolar disorder were nearly seven times as likely to develop Parkinson’s disease as people who did not have bipolar disorder.

The people with bipolar disorder who developed Parkinson’s disease did so at a younger age than the control group members who developed the disease—64 years old at diagnosis compared to 73 years old.

People who were hospitalized more often for bipolar disorder were more likely to develop Parkinson’s disease than those who were hospitalized less than once per year. A total of 94 percent of those with bipolar disorder were hospitalized less than once per year; 3 percent were hospitalized one to two times per year; and 3 percent were hospitalized more than two times per year. Those who were hospitalized more than two times per year were six times more likely to develop Parkinson’s disease than those who were hospitalized less than once per year. People who were hospitalized one to two times per year were four times more likely to develop Parkinson’s disease than those who were hospitalized less than once per year.

The people with bipolar disorder who developed Parkinson’s disease did so at a younger age than the control group members who developed the disease—64 years old at diagnosis compared to 73 years old.

“Further studies are needed to investigate whether these diseases share underlying processes or changes in the brain,” Chen said. “These could include genetic alterations, inflammatory processes or problems with the transmission of messages between brain cells. If we could identify the underlying cause of this relationship, that could potentially help us develop treatments that could benefit both conditions.”

A limitation of the study is it included only people who sought medical help for their bipolar disorder. Also, the database did not include information on family history of Parkinson’s disease or environmental factors that could increase people’s risk of developing the disease.

 
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Brain discovery explains a great mystery of Parkinson's

University of Virginia | Feb 15, 2019

One of the great mysteries of neuroscience may finally have an answer: Scientists at the University of Virginia School of Medicine have identified a potential explanation for the mysterious death of specific brain cells seen in Parkinson's.

The new research suggests that the cells may die because of naturally occurring gene variation in brain cells that were, until recently, assumed to be genetically identical. This variation -- called "somatic mosaicism" -- could explain why dopaminergic neurons are the first to die in Parkinson's.

"This has been a big open question in neuroscience, particularly in various neurodegenerative diseases," said neuroscientist Michael McConnell, PhD, of UVA's Center for Brain Immunology and Glia (BIG). "What is this selective vulnerability? What underlies it? And so now, with our work, the hypotheses moving forward are that it could be that different regions of the brain actually have a different garden of these [variations] in young individuals and that sets up different regions for decline later in life."

A most unexpected outcome

The finding emerged unexpectedly from McConnell's investigations into schizophrenia. It was in that context that he and his collaborators first discovered the unexpected variation in the genetic makeup of individual brain cells. That discovery may help explain not just schizophrenia but depression, bipolar disorder, autism and other conditions.

Continuing his investigations, McConnell expected that this mosaicism would increase with age -- that mutations would accumulate over time. What he and his collaborators at Johns Hopkins found is exactly the opposite: Younger people had the most mosaicism and older people had the least.

"We wound up building an atlas that contained neurons from 15 individuals. None of these individuals had disease," said McConnell, of UVA's Department of Biochemistry and Molecular Genetics and UVA's Department of Neuroscience. "They ranged in age from less than a year to 94 years, and it showed a perfect anti-correlation with age."

Based on the finding, McConnell believes that the neurons with significant genetic variation, known as CNV neurons, may be the most vulnerable to dying. And that could explain the idiosyncratic death of specific neurons in different neurodegenerative diseases. People with the most CNV neurons in the temporal lobe, for example, may be likely to develop Alzheimer's.

More work needs to be done to fully understand what's occurring, McConnell said. So far, he has only looked at neurons in the frontal cortex of the brain, and his studies are limited by the fact that neurons can be examined only after death, so it can be hard to make direct comparisons. But he is excited to expand the scope of his research.

"Because I'm collaborating with the Lieber Institute and they have this fantastic brain bank, now I can look at individuals' frontal cortex, for the schizophrenia research, and I can look at the temporal lobe in those same individuals," McConnell said. "So now I can really start to map things out more carefully, building an atlas of different brain regions from many individuals."

That research could greatly advance our understanding of both neurodegenerative diseases and the cognitive decline that besets us with age, potentially leading to new treatments.

"What's really interesting about mosaicism is that it is fundamentally tweaking our assumptions about what nature is, because we've kind of always assumed that every cell in any given individual had the same genome, the same DNA in every cell," McConnell said. "And now we're showing that it's different and what that might mean."

https://www.sciencedaily.com/releases/2019/02/190215135835.htm
 
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mr peabody

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Ibogaine and Parkinson’s

European Ibogaine Forum | 10 Sep 2017

GDNF (glial cell line-derived neurotrophic factor) is a protein discovered in 1991 with an extraordinarily positive effect on nerve cell tissue. GDNF stimulates nerve cell growth, especially dopamine neurons. In addition to the ability to regenerate nerve cells in the brain, GDNF also appears to possess neuroprotective properties.


In an animal experiment in which rats with Parkinson’s disease had GDNF injected directly into the brain, a significant improvement in the symptoms was observed. After one year, there were still no undesirable side effects of GDNF administration. Initial studies have shown that GDNF significantly improves the overall condition of Parkinsonian patients. The resulting data suggests that new nerve cells had formed.

Ibogaine and its metabolite noribogaine lead to a substantial increase in GDNF levels in the brain. This indicates that ibogaine could provide a very effective treatment for neurodegenerative diseases, such as Parkinsons.

Until now, it was not possible to introduce GDNF directly into the desired regions of the brain. But Ibogaine stimulates the glial cells and neurons to produce GDNF itself, increasing GDNF levels throughout the brain.

 Phytostan, a pharmaceutical company focused on developing ibogaine, has developed an ibogaine-based medicine called CK-BR 12. This consists of Ibogaine HCL and a cocktail composed of 12 vitamins.

Patient D is a 69-year-old Parkinson’s disease patient and until now the only human treated with Ibogaine for his condition. Patient D reported numerous positive changes regarding his illness: he could swallow again, speech and facial expressions improved, the control of the hands increased and he could write again legibly. Also, his general motor skills increased.

He could dress again, eat independently and climb stairs – all activities which were not possible prior to his treatment. The Parkinson’s symptomatology also improved after the treatment was completed. Patient D. was examined by various physicians as well as pharmacologist Dr. Susanne Cappendijk from Semper Clarus Consulting, who presented the promising results at the New York Academy of Sciences.

The standard symptomatic treatment, is predominantly carried out with drugs with strong side effects. The quality of life of the patients is often characterised by significant suffering in the terminal phase. In contrast, treatment with ibogaine, in particular through the approach of microdosing, allows an increase in the GDNF levels in the brain, without the side effects of conventionally used medications.

It was reported that 4mg Ibogaine HCL can increase GDNF levels in the brain by a factor of 12. The neuroplasticity increased by the growth of new neurons promotes the restoration and the construction of nerve tracts. Also, the challenge of introducing GDNF by injection into the brain is obviated. These results could help to redefine the position of Ibogaine in general research and – as ever-unknown healing properties of the plant are discovered – open up new research areas and thereby achieve a wider social and regulatory acceptance.

Novel variations of the ibogaine molecular structure have been developed that enhance the production of GDNF. The group of N-indolylethyl isoquinuclidines appears to be most promising. The synthesis of these molecules is far less complex than that of Ibogaine and there are several promising derivatives. Some of the analogues cause an even higher GDNF-release in vitro than Ibogaine does, but can have cytotoxic effects depending on the structure. The research in this field is still nascent, but it has enormous potential.

http://iboga.info/parkinsons-disease/
 
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New research shows that Parkinson’s originates in the gut

Neuroscience News | June 26, 2019

In experiments in mice, Johns Hopkins Medicine researchers say they have found additional evidence that Parkinson’s disease originates among cells in the gut and travels up the body’s neurons to the brain. The study, described in the June issue of the journal Neuron, offers a new, more accurate model in which to test treatments that could prevent or halt Parkinson’s disease progression.

“These findings provide further proof of the gut’s role in Parkinson’s disease, and give us a model to study the disease’s progression from the start,” says Ted Dawson, M.D., Ph.D., director of the Johns Hopkins Institute for Cell Engineering and professor of neurology at the Johns Hopkins University School of Medicine.

Parkinson’s disease is characterized by the buildup of a misfolded protein, called alpha-synuclein, in the cells of the brain. As more of these proteins begin to clump together, they cause nerve tissues to die off, leaving behind large swaths of dead brain matter known as Lewy bodies. As brain cells die, they impair a person’s ability to move, think or regulate emotions.

"The new study builds off observations made in 2003 by German neuroanatomist Heiko Braak that showed people with Parkinson’s disease also had accumulations of the misfolded alpha-synuclein protein in the parts of the central nervous system that control the gut. The appearance of these neuron-damaging proteins is consistent with some early symptoms of Parkinson’s disease, which include constipation," says Hanseok Ko, Ph.D., associate professor of neurology at the Johns Hopkins University School of Medicine. Braak hypothesized that "Parkinson’s disease advanced up the nerves connecting the gut and the brain like going up a ladder."

A growing body of evidence has implicated the gut-brain connection in initiating Parkinson’s disease. The researchers were most curious whether the misfolded alpha-synuclein protein could travel along the nerve bundle known as the vagus nerve, which runs like an electrical cable from the stomach and small intestine into the base of the brain.

To test this, the researchers injected 25 micrograms of synthetic misfolded alpha-synuclein created in the lab into the guts of dozens of healthy mice. The researchers sampled and analyzed the mouse brain tissue at one, three, seven and 10 months after injection. Over the course of the 10-month experiment, the researchers saw evidence that the alpha-synuclein began building where the vagus nerve connected to the gut and continued to spread through all parts of the brain.

"The researchers then conducted a similar experiment, but this time surgically cut the vagus nerve in one group of mice and injected their guts with the misfolded alpha-synuclein. Upon examination at seven months, the researchers found that mice with severed vagus nerves showed none of the signs of cell death found in mice with intact vagus nerves. The severed nerve appeared to halt the misfolded protein’s advances," says Dawson.

The researchers then investigated whether these physical differences in Parkinson’s disease progression resulted in behavioral changes. To do this, they evaluated the behavior of three groups: mice injected with misfolded alpha-synuclein, mice injected with misfolded alpha-synuclein with cut vagus nerves, and control mice with no injection and intact vagus nerves. The researchers looked at tasks they commonly used to distinguish signs of mouse Parkinson’s disease, including nest building and exploring new environments.

The researchers first observed the mice build nests in their enclosure as a test for fine motor dexterity, which is commonly affected by Parkinson’s disease in humans. Healthy mice often make large, dense mounds in which to burrow. Smaller, messier nests are often signs of problems with motor control.

Seven months after injection, the researchers provided the mice with nesting materials and observed their nest building behavior for 16 hours, scoring their capabilities on a scale of 0-6. They found that mice that received the misfolded alpha-synuclein injection scored consistently lower on nest building.

"While the control and severed vagus nerve groups consistently scored 3 or 4 on the nest building scale, mice that received the misfolded alpha-synuclein scored lower than 1. Also, while most mice used the entire 2.5 grams of material provided, the group of mice that received the alpha-synuclein injection used less than half a gram of the nesting material. In ways similar to Parkinson’s disease symptoms in humans, the mice’s fine motor control deteriorated as the disease progressed," says Ko.

In another experiment analyzing the mice for symptoms similar to Parkinson’s disease in humans, the researchers measured anxiety levels of the mice by monitoring how they responded to new environments.

For this test, the researchers placed the mice in a large open box where a camera could track their exploration. Healthy mice are curious and will spend time investigating every part of a new environment. However, mice affected by cognitive decline are more anxious, causing them to be more likely to stay toward the sheltered edges of a box.

The research team found that control mice and mice that had their vagus nerves cut to protect against Parkinson’s disease spent between 20 and 30 minutes exploring the center of the box. On the other hand, mice that received the misfolded alpha-synuclein injection but had intact vagus nerves spent less than five minutes exploring the center of the box and moved mostly around the borders, indicating higher anxiety levels, which the researchers report are consistent with symptoms of Parkinson’s disease.

In experiments in mice, Johns Hopkins Medicine researchers say they have found additional evidence that Parkinson’s disease originates among cells in the gut and travels up the body’s neurons to the brain. The study offers a new, more accurate model in which to test treatments that could prevent or halt Parkinson’s disease progression.

Overall, the results of this study show that misfolded alpha-synuclein can be transmitted from the gut to the brain in mice along the vagus nerve, and blocking the transmission route could be key to preventing the physical and cognitive manifestations of Parkinson’s disease.

“This is an exciting discovery for the field and presents a target for early intervention in the disease,” says Dawson.

Next, the researchers say, they plan to explore what parts of the vagus nerve allow the misfolded protein to climb to the brain, and to investigate potential mechanisms to stop it.

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Is the appendix a contributing factor in the development of Parkinson’s?

by Freya Harrison | 12 Dec 2018

We all learnt it growing up: the appendix is a useless relic from our evolutionary past, only used to help digest the bark we consumed as cave men and women. But research has now identified this (often dismissed) organ’s role in monitoring pathogens in the immune system. What’s more, it may even play a part in the development of Parkinson’s disease.

Emerging research, published October 2018, saw Labrie and colleagues at the Van Andel Research Institute analyse data from nearly 1.7 million Swedes over 50 years. During this longitudinal study, removal of the appendix in early adulthood resulted in a 19 percent decrease in the risk of developing Parkinson’s disease in later life.

…removal of the appendix in early adulthood resulted in a 19 percent decrease in the risk of developing Parkinson’s disease in later life.

Parkinson’s disease (PD) is a neurodegenerative condition which results in a wide variety of physical and psychological symptoms, including involuntary shaking, stiff muscles, memory problems, and sometimes even the loss of senses. Parkinson’s affects over 10 million people globally, and yet the causes are still unknown – making it a critical research topic. While the causal factor is yet to be firmly identified, the disease is often associated with an abnormal ‘clumping’ of alpha-synuclein protein, and subsequent neuron death, within the substantia nigra (a brain structure critical to movement). Interestingly, pre-clinical symptoms of Parkinson’s disease may be evident long before diagnosis – symptoms found in the gut.

Research now reveals that these ‘protein clumps’ are found in abundance within the human appendix, potentially providing evidence for the involvement of this organ in the development of Parkinson’s. But how do these abnormal aggregations travel from the gut to the brain?

The gut-brain axis, a two-way system involved in communication between the central nervous system and gastrointestinal tract, is now believed to be involved in the transmission of PD symptoms from the gut to the brain. Evidence suggests pro-inflammatory bacteria may increase gut permeability, enabling the ‘leakage’ of the abnormal alpha-synuclein protein, which then travels via the gut-brain axis to the central nervous system.

So, what are the implications of these findings? Clearly the appendix is not the whole story (or appendectomy patients would never suffer from Parkinson’s), but research does provide evidence of a possible ‘breeding ground’ of PD in the gut, and highlights the importance of gut health for neurological and behavioural maintenance. Labrie and colleagues stated, “preventing excessive alpha-synuclein clump formation in the appendix, and its departure from the gastrointestinal tract, could be a useful new form of therapy.” Some researchers even speculate that diet is the key, that food-based remedies may be the future of neurodegenerative disease management.

 
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Ibogaine and Parkinson's

Parkinson’s Disease is classified as a neurodegenerative disorder, one characterized by the progressive atrophy of the central and peripheral nervous system. However, some evidence suggests that the neurodegeneration in Parkinson’s subjects may be caused by the body’s own immune system losing the ability to determine between healthy and unhealthy cells, as is the case with autoimmune diseases such as Fibromyalgia, Multiple Sclerosis and others, in which much of the body’s organs and cell tissue deteriorate because of misdirected attack by the immune system.

Although the theory is still untested, there is anecdotal evidence and a theoretical framework that suggests ibogaine may have therapeutic benefits in the treatment of Parkinson, and possibly other disorders that cause the degeneration of brain and cell tissues.

The theoretical case is based on the fact that both ibogaine and its metabolite noribogaine have been shown to lead to an increase in levels of glial cell line-derived neurotrophic factor (GDNF) in the brain. It has also been shown to have neuroprotective qualities promoting the survival of both dopaminergic and motor neurons.

In other research, neutrophic factors, specifically GDNF, have been shown to cause sprouting of dopaminergic fibers, with a resulting improvement of clinical symptoms of Parkinson’s in experimental animal models and humans. However, there is little research available using neutrophic factors in the treatment of other neurodegenerative disorders, particularly because administration is usually limited by toxicity or poor bioavailability. Various other methods of administration such as direct brain infusion of GDNF and gene therapy that promotes the expression of neurotrophic factors have been explored.

The direct brain infusion of GDNF into the brains of five rats induced with Parkinson’s disease showed a 39% improvement in off-medication motor sub-score of the Unite Parkinson’s Disease Rating Scale (UPDRS), and a 61% improvement in the activities of daily living sub score. After one year, no side effects from the treatment were observed.

In addition to Parkinson’s, one study using gene therapy that promotes the expression of neurotrophic factors, showed a 50% increase in life span, reduced loss of motor axons and improved neuromuscular function in animal models representing Motor Neuron Diseases. The study suggested further research into neurotrophic factor as a treatment for MND.

Parkinson’s and similar diseases have no known cure, and these conditions often require management with drugs that have considerable side effects, causing a very poor quality of life for terminal stage sufferers of these diseases.

Ibogaine therapy, especially low-dose regimens, may facilitate the expression of GDNF without the side effects of other medications or the difficulty of other avenues of administering neurotrophic factor. Anecdotal reports suggest that at least several people with Parkinson’s who have been treated with ibogaine have seen an extended remission of symptoms.

Although there is little clinical research into this particular application, one of the first studies to assess ibogaine efficacy, specifically in the treatment of Parkinson's disease in animal models, is currently underway at Columbia University.

https://www.ibogainealliance.org/ibo...py/parkinsons/
 

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The latest study was prompted by the experiences of a former stuntman, Tim Lawrence. He made headlines when he claimed in a BBC TV documentary that “E” enabled him to regain control of his body for hours at a time.
That was indeed a remarkeable documentary. I watched him experience his 5 hours of normalness on MDMA.

Doing gymnastics and enjoying the .. out of it. After the XTC took his course the Parkinson returned giving him a short holiday from the disease.
 

mr peabody

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LSD and Parkinson's

In a very real sense the circle is closing with respect to Albert Hofmann's hope, expressed at the time of his discovery of LSD. Because of its psychotomimetic action (ability to mimic certain mental illnesses), the drug might prove useful in their treatment. In fact, LSD has been employed to that end over the years by some psychiatrists, often with beneficial results.

Recently, scientists at the School of Medicine of the University of California at Los Angeles have made some significant discoveries about the interaction of LSD with dopamine, one of the neurotransmitter agents in the brain, that may lead not only to a better understanding and eventual treatment of schizophrenia, the mental disorder to which the LSD "high" is a kind of temporary analogue, but even of such physically, rather than mentally, crippling disorders as Parkinson's disease. The investigators, Drs. Sidney Roberts and Kern von Hungen and Diane F. Hill, determined that adenyl cyclase, an enzyme in nervous tissue that is stimulated by naturally occurring neurotransmitter agents, is also stimulated by the action of LSD on receptors for one of these neurotransmitters, dopamine. In addition, LSD blocked the stimulatory actions of dopamine and other neurotransmitters such as serotonin and norepeninephrine. These are themselves structurally closely related to powerful plant growth hormones; dopamine, moreover, has also been identified with the giant saguaro cactus of Arizona and northern Mexico.

Schizophrenia is thought to be a disease of dopamine hyperactivity; victims of Parkinson's disease, on the other hand, suffer from dopamine insufficiency, which is partially offset nowadays by the administration of a new drug, L-dopa, often in combination with Tofranil or some other amphetamine. The adenyl cyclase experiments enabled the UCLA team to show that dopamine receptors are present in the higher regions of the brain, which are concerned with the more complex experiences and thus are more likely to be the seat of alternate states of consciousness, or "hallucinations." Their work, report the UCLA investigators, makes it appear that the psychotic mimicking effects of LSD, first noted by Hofmann more than thirty years ago, may also be related to hyperactivity of brain dopamine systems. These insights have obvious implications for work on new drugs for schizophrenia on the one hand and Parkinson's disease on the other; recognition of their biochemical kinship was, of course, still far off in the distant future when Hofmann correctly predicted the ultimate benefits of LSD for brain research. Nor did he suspect at the time that "primitive" psychotherapy had been making effective use of a natural compound very like LSD for hundreds, perhaps thousands, of years.

"Lysergic acid," Hofmann (1967) has explained, "is the foundation stone of the ergot alkaloids, the active principle of the fungus product ergot. Botanically speaking ergot is the sclerotia of the filamentous fungus Claviceps purpurea which grows on grasses, especially rye. The ears of rye that have been attacked by the fungus develop into long, dark pegs to form ergot. The chemical and pharmacological investigation of the ergot alkaloids has been a main field of research of the natural products division of the Sandoz laboratories since the discovery of ergotamine by A. Stoll in 1918. A variety of useful pharmaceuticals have resulted from these investigations, which have been conducted over a number of decades. They find wide application in obstetrics, in internal medicine, in neurology and psychiatry."

https://www.drugtimes.org/hallucinogens-culture/
 
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mr peabody

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Low vitamin D levels linked to symptoms in patients with Parkinson’s disease

Neuroscience News | Aug 7 2019

Vitamin D deficiency is widespread in patients with Parkinson’s disease (PD). Our aim was to determine whether serum vitamin D levels correlated with bone mineral density (BMD) and non‐motor symptoms in patients with PD.

In an Acta Neurologica Scandinavia study of 182 patients with Parkinson’s disease and 185 healthy controls, patients with Parkinson’s disease had significantly lower levels of vitamin D in their blood. Also, patients with lower vitamin D levels were more likely to fall, and to experience sleep problems, depression, and anxiety.

The findings suggest that vitamin D supplementation may help to treat non-motor symptoms associated with Parkinson’s disease.

“As various non-motor symptoms place a burden on individuals with Parkinson’s disease and their caregivers, vitamin D might be a potential add-on therapy for improving these neglected symptoms,” said senior author Chun Feng Liu, MD, PhD, of the Second Affiliated Hospital of Soochow University, in China.

Patients with PD had significantly lower serum levels relative to healthy controls. After adjusting for age, sex, and body mass index, vitamin D levels significantly correlated with falls, insomnia, and scores for the PSQI, depression, and anxiety.

Conclusions

In patients with PD, vitamin D levels significantly correlated with falls and some non‐motor symptoms. However, no associations were found between BMD and the serum levels in patients with PD. Thus, vitamin D supplementation is a potential therapeutic for non‐motor PD symptoms.

 
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mr peabody

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Is ibogaine a promising new treatment for Parkinson's?

by Jonathan Dickinson | Ibogaine Alliance

A research team at Columbia University soon hopes to show whether or not ibogaine, an extract of iboga, a psychoactive West-African plant medicine, may have unique benefits in the treatment of Parkinson's disease. The majority of existing research on ibogaine has explored its increasing use over the past several decades as an experimental treatment for substance use disorders, and particularly for opiate detoxification. But in addition to ibogaine's anti-addictive properties, which have been explored in early clinical trials and observational research, there's reason to believe that ibogaine may be beneficial in Parkinson's treatment. Columbia's two-year animal study represents the first time that researchers will probe for a direct link. Parkinson's disease, which is recognized as the second most common neurodegenerative disorder after Alzheimer's, is caused by the loss of a specific type of brain cells called dopaminergic neurons from a small and concentrated area in the mid-brain. This results in gradually increasing symptoms that include motor effects like tremors, muscle stiffness, difficulties with speech, severe lack of coordination and balance, as well as non-motor symptoms such as dementia, depression and others.

According to the Parkinson's Disease Foundation the condition affects an estimated 7 to 10 million people worldwide. And although treatments are available that offer some symptomatic relief, there is currently no known method of reversing the effects of the disease.

The exact mechanisms of action of ibogaine are still obscure, but the theory for ibogaine's benefit for Parkinson's rests on the fact that amongst its other effects, it has been shown to increase the production of a protein called glial cell-derived neurotrophic factor, or GDNF. This and other neurotrophic factors have been shown to stimulate the production of dopaminergic fibers throughout the brain, and some existing research shows that GDNF in particular improves the recovery of dopaminergic neurons and leads to an improvement of Parkinson's symptoms.

Previous methods used to increase the expression of GDNF were limited gene therapy and direct brain infusion, but according the research abstract, the research team, led by Dr. Serge Przedborski, President of the World Parkinson Coalition, is exploring whether ibogaine could provide "a safer and more convenient means to enhance GDNF production in the brain."

Ibogaine's Clinical Development

Tabernanthe iboga, ibogaine's primary plant source, has been used for millennia in Gabon and other parts of West Africa as a medicine and initiatory sacrament. In 1962, a 19-year-old named Howard Lotsof was the first Westerner to discover that ibogaine, iboga's primary active ingredient, could mitigate withdrawals from opiates, and provide unique psychological benefits including relief from cravings for many who take it.

Lotsof's later advocacy work during the late eighties and early nineties resulted in the U.S. National Institutes of Health (NIH) funding early clinical trials. While this proved a promising and uncharacteristic support for public research, the NIH eventually withdrew funding because of the complexity of the trials and litigation between the investigators.

Despite the lack of funding for clinical development, the research that has been done has continued to be supportive. Some researchers believe that ibogaine's release of GDNF may play a role in its more lasting psychological benefits by potentiating a state of neuroplasticity that some refer to as a kind of "neurological second childhood." To some extent, the rapid growth of new neurons may help to repair and rebuild neurological pathways that have been damaged by addiction.

Years later, several research teams are slowly preparing Phase 1 and 2 trials on human patients to continue to explore ibogaine's use in addiction treatment. Re-initiating those trials has remained difficult for many reasons, partly because there is little profit motive for pharmaceutical drug developers, and to some extent due to reports of fatalities that have occurred in close conjunction with ibogaine administration.

The risks involved in ibogaine addiction treatment stem largely from the fact that it is unregulated and there are huge variations in the level of care provided at ibogaine treatment centers. However, many therapy providers and researchers agree that its use can be made safe with proper screening and in-treatment monitoring.

One of those doctors, Dr. Jeffrey Kamlet, a Miami medical doctor and board certified addiction specialist has been researching ibogaine for over 20 years, and is a strong advocate for medical supervision. According to Dr. Kamlet, "Ibogaine is the most important discovery in the field of opiate dependency in the history of addiction medicines, and I'm confident that it will one day be a main stay treatment for many addictions."

Even with this in mind, some advocates believe that ibogaine's application as a treatment for Parkinson's may prove more straightforward for research. In the case of addiction therapy, ibogaine is most often administered in a single large dose, but there is anecdotal evidence that the repeated use of very low sub-perceptual doses, which are generally agreed to be well tolerated in patients, could be sufficient to reverse Parkinson's symptoms over time.

One Promising Case

Patient D* was 69 years old in 2012 when he was diagnosed with Atypical Parkinson's, a Parkinson's-like syndrome that does not include the characteristic palsy. By last year Patient D's symptoms had advanced to the point where his facial muscles felt frozen. He had difficulty finding his balance, talking or using his hands. As a writer and artist, he noted that emotionally it was the first time in his life he had lost his desire to do anything creative.

In December 2014, Patient D was treated with CKBR-12, an experimental natural health product and "ibogaine-derivative" at a medical center in Rosarito, Mexico. He took a small dosage twice a day for 30 days, and after the first two weeks began to notice that he could use his fingers to pick up objects again. After a month he had seen a gradual improvement in all of his symptoms to the point where he could carry on normal conversation, and coordinate previously impossible tasks such as buttoning his shirt.

In a post-treatment interview that was published on YouTube, Patient D says, "It's difficult to explain what Parkinson's is, but you lose your edge. And I've got my edge back in a few areas. They may be small things to some, but they are big things for me. I'm anxious to see what happens next."

When we spoke, to Patient D, he said that he had continued to have improvements with further treatment. His case has been reviewed by several doctors, including Dr. Susanne Cappendijk of Florida State University Medical Center, who relayed some of the results at a conference at the New York Academy of Sciences on April 27th.

Ibogaine as a Prescription Medicine

Much like ibogaine's use in addiction treatment, the current use of ibogaine for Parkinson's and other neurodegenerative disorders is illegal in the U.S. due to its Schedule 1 status. In most countries, including Canada and Mexico, this is not the case. Yet, even in places where ibogaine can be administered, treatments are considered experimental until they undergo the full battery of demanding clinical trials.

This widening berth of ibogaine research may help to build a more encouraging case for its approval as a prescription medicine. But even if both applications hold efficacy, as long as one is granted FDA approval, the other could speculatively be administered "off-label."

The clinical trial process is bulky and challenging for many medications, including useful new antibiotics, because they cost millions and are slow to develop. If medications that are advantageous from a public health perspective don't come packaged with a lucrative business plan there few big pharmaceutical companies willing to invest. One of the main reasons that ibogaine hasn't been funded by the existing addiction treatment industry is that it is only administered once, or a few times, rather than as an ongoing regimen.

In 2009, New Zealand became the first country in the world to offer ibogaine as a prescription on an experimental basis, a trend that may eventually follow elsewhere. Now, in Vermont, addiction rates have become so severe that the governor dedicated his entire State of the State speech to the issue. This prompted members of the Vermont State Legislature to table a bill that would allow the operation of a non-profit ibogaine detox center in the state. The bill could find its way to the governor's desk as early as next year.

Even in the midst of these isolated examples, and without broad regulatory reform, FDA approval is needed to make ibogaine treatments more widely available. Researchers who are studying ibogaine for addiction treatment have to look past a $35 billion U.S. addiction treatment industry that believes it possesses effective modalities, even despite a general increase in rates of addiction. Parkinson's researchers, on the other hand, may have the benefit of a number of large foundations that are established to fund research in yet another field where few other drugs can claim similar promise.

https://www.ibogainealliance.org/news/could-ibogaine-be-a-promising-new-treatment-for-parkinsons-disease/
 
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mr peabody

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Clinical trial to repurpose ketamine for Parkinson's*

By Maria Cohut | Medical News Today | 20 July 2018

The drug used to manage some of the most salient symptoms of Parkinson's disease is known to expose patients to more motor issues, as part of its side effects. Researchers suggest that ketamine could be used to neutralize those side effects.

Parkinson's disease, a motor system disorder, is characterized by tremor, limb stiffness, impaired balance, and slowness of movement, as well as impaired movement coordination.

There is currently no known cure for this disorder, so treatments focus largely on managing the symptoms.

This helps people maintain autonomy and quality of life, as much as possible.

One of the main drugs used to treat Parkinson's disease is levodopa, which can help with limb stiffness and slowness of movement. But there is a caveat: patients for whom levodopa does work begin to experience potentially debilitating side effects after a few years on the drug.

"The problem is levodopa works great for a few years — we call that the 'honeymoon' period — but then you start getting these side effects," notes Dr. Scott Sherman, a neurologist at the University of Arizona College of Medicine in Tucson.

So what happens to many patients who take levodopa? They develop dyskinesia, or involuntary and uncontrollable movements that can affect the limbs, the head, or even the entire body, to various degrees of severity.

Once an individual develops levodopa-related dyskinesia, it does not go away unless treatment with this drug is discontinued altogether — though this may mean that their symptoms will no longer be managed.

But is there anything that could counteract levodopa's side effects? Dr. Sherman and colleague Torsten Falk believe that the answer may lie with ketamine.

Ketamine's effect on dyskinesia

Dr. Sherman and Falk found the first clues about ketamine's potential in offsetting dyskinesia when they tested it as a pain-relieving drug for patients with Parkinson's.

Their trial led them to observe an unintended yet welcome effect: dyskinesia was ameliorated, or even disappeared completely for a few weeks in the case of individuals on levodopa who were also administered ketamine.

When the researchers tried to duplicate these findings in a rat model, they found that the dyskinesia-offsetting effects of ketamine held strong.

This has led them to plan a controlled clinical trial in the hopes of discovering how — or whether — ketamine might best be used in conjunction with levodopa to treat patients with Parkinson's disease.

Ketamine's best-known side effect is dissociation (also known as disassociation), in which a person feels as though they are perceiving the world from some place outside of their own bodies. This uncanny effect is also why ketamine has notoriously been misused as a "party drug."

"Disassociation is a sort of 'out-of-body' experience. When people describe it, they have told me that they feel like they are in fish bowl," explains Dr. Sherman.

Another common risk of taking ketamine is raised blood pressure. However, the scientists are strategizing to keep these possible effects in check by carefully calculating dosage.

According to Dr. Sherman, "We are going to monitor blood pressure closely to make sure it doesn't get high. And," he continues, "we know at what dosage ketamine causes this disassociation; we expect that the dosage needed in Parkinson's disease will stay well below that level."

"Ketamine has been long overlooked. Now it could prove very useful for Parkinson's patients,"
said Dr. Sherman.

*From the article here:

 
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