MS | +50 articles

[mr peabody]

Vitamin D deficiency linked to MS

Neuroscience News | April 17, 2019

Scientists have uncovered fresh insights into how vitamin D affects the immune system and might influence susceptibility to diseases such as multiple sclerosis.

Vitamin D is produced by the body in response to sunlight and is often lauded for its health benefits. Researchers found it also affects key cells of the immune system.

This discovery might explain how vitamin D regulates immune reactions that have been implicated in autoimmune diseases such as MS.

The University of Edinburgh team focused on how vitamin D affects a mechanism in the body’s immune system – dendritic cells’ ability to activate T cells.

In healthy people, T cells play a crucial role in helping to fight infections. In people with autoimmune diseases, however, they can start to attack the body’s own tissues.

By studying cells from mice and people, the researchers found vitamin D caused dendritic cells to produce more of a molecule called CD31 on their surface and that this hindered the activation of T cells.

Scientists at the University of Edinburgh have uncovered fresh insights into how vitamin D affects the immune system. They found it prevents key cells called dendritic cells and T cells from forming a stable contact. This hinders their activation and greatly reduces the immune reaction. The team says this might explain why people who are deficient in vitamin D may be more susceptible to diseases such as multiple sclerosis, which occur when the immune system attacks the body’s own tissues.

The team observed how CD31 prevented the two cell types from making a stable contact – an essential part of the activation process – and the resulting immune reaction was far reduced.

Researchers say the findings shed light on how vitamin D deficiency may regulate the immune system and influence susceptibility to autoimmune diseases.

Professor Richard Mellanby, of the University of Edinburgh’s Centre for Inflammation Research, said: “Low vitamin D status has long been implicated as a significant risk factor for the development of several autoimmune diseases. Our study reveals one way in which vitamin D metabolites can dramatically influence the immune system.”

Vitamin D study sheds light on immune system effects - Neuroscience News

Vitamin D causes dendritic cells to produce more CD31, hindering the activation of T cells. The study sheds light on how vitamin D deficiency regulates the immune system and can lead to autoimmune diseases, like multiple sclerosis.

neurosciencenews.com

 

[mr peabody]

MS patient calls medical cannabis trial 'a miracle'

The Montreal study, now in Phase 2, will try to determine if cannabis can be used as a less-dangerous substitute for opiate-based painkillers.

By the time she decided to try cannabis pills, Joanne Fiorito was in dire straits. Fiorito could barely lift her feet when she walked and sometimes used an electric wheelchair to get around. Occasionally she'd wake up in the middle of the night, riddled with pain from her tensing muscles. The 61 year old has lived with multiple sclerosis for most of her life and, despite her use of heavy doses of painkillers and muscle relaxants, the symptoms were only getting worse. Last winter her neurologist suggested she take a chance and participate in a clinical trial on medical cannabis.

"I had nothing to lose," Fiorito said. "The cannabis was like a miracle. Within three days my legs were less stiff, they didn't feel as heavy. At physiotherapy, they timed me for six minutes to see how far I can walk. In October I did 89 meters. This week, it was 251 meters. I'm not joking when I say it"s like a miracle."

Fiorito is one of 70 Montreal-area patients participating in a clinical trial for medicinal cannabis capsules. The study, which entered its second phase last April, will try to determine if cannabis can be used as a less-dangerous substitute for opiate-based painkillers. If it's successful - and the capsules are approved by Health Canada's Office of Controlled Substances - cannabis could be sold in pharmacies and covered by provincial health insurance. The study is a partnership between Montreal's Sante Cannabis clinic and the Ottawa-based Tetra Pharma Bio. It mainly focuses on people with chronic pain and cancer pain who have never tried medical cannabis before.

"This is about giving people like Joanne (Fiorito) a chance to access medicine that is quality-controlled and affordable," said Erin Prosk, the co-founder of Sante Cannabis. "The medical cannabis system we have now is not enough. It's a Band-Aid, a temporary solution."

Canada's medical cannabis system has existed under its current form for only four years. Each of the roughly 250,000 patients with prescriptions can order weed online from one of 115 producers licensed by the federal government. But unlike with the vast majority of medicines, cannabis isn't covered by health insurance. In fact, patients have to pay sales tax on it. Adding to patients' financial burden, the Cannabis Act, which will legalize the sale of recreational pot starting Oct. 17, actually adds a 10-per-cent excise tax for medical cannabis users.

"The Cannabis Act is causing collateral damage in our world," said Prosk. "Some people think that with legalization, patients can just go to the store and buy cannabis. But the people who use medical cannabis need a specific pharmaceutical-grade product to treat specific symptoms."

In the study, patients are either given a placebo or capsules that contain a high concentration of two cannabinoids; tetrahydrocannabinol (THC), which has a psychoactive and pain-numbing affect, and cannabidiol (CBD), which can be used as an anti-inflammatory, a muscle relaxant and to treat epilepsy. Thus far, only one of the 70 patients recruited has reported experiencing severe side effects from the drug.

"Except for that one case, where the patient wasn't able to tolerate it, everyone has been tolerating it quite well," said Dr. Antonio Vigano, who is leading the trial. "I was surprised at how tolerable it was, at how safe it was. That's the main concern, when you do these trials, is to make sure the product is safe."

For the first phase of the study, patients were given a low dose of the CBD and THC pills so their bodies could adjust to the drug. Vigano says that, for some, it was enough to notice a difference in pain management. Gradually, the doctors increase patient doses until they reach a point where the medicine takes affect.

"Our theory was that starting low and increasing slowly is really important to increase that tolerability," said Vigano, an associate professor of oncology at McGill University. "That's what we're seeing in practice. It's encouraging."

Prosk has been on the forefront of the fight to increase access to medical marijuana for years and says cannabis research is still in its infancy. As her clinic's study is underway, the University of British Columbia is leading a trial on the use of medicinal pot for people who struggle with post-traumatic stress disorder.

"Considering where we were four years ago, just getting the system to license cannabis producers off the ground, it's unreal how far we've come," said Prosk. "We're global leaders in cannabis research, and we,re getting interest from international companies. Countries like Germany and Australia are looking to Canada for leadership."

"There's huge potential here and the right people are finally taking notice."

Sante Cannabis and Tetra Pharma Bio still have reams of data to study and there are many more roadblocks on the way to having their product approved. But Prosk says the future looks promising. For Fiorito, the clinical trial has been a lifesaver.

"I used to wake up in the night, screaming in pain," she said. "I'm not waking up at night anymore. I'd say 80 per cent of the pain is gone."

"Last year, I felt like the wheelchair was pretty close to my ass if I may say so. I felt like, 'Oh she's really gaining on me, I'll be stuck in that wheelchair for the rest of my life.' Last week, my neurologist said he hadn't seen me move like that in years. It's a miracle."

https://montrealgazette.com/news/mul...rial-a-miracle​

 

[mr peabody]

Cambridge

Do psychedelics affect MS attacks?

by Eric Valor

In the case of LSD specifically, no.

Other recreational drugs might affect your immune function but LSD doesn't. MS is a problem of the immune system specifically called an "Auto-Immune Disorder" where the immune system starts making antibodies against certain cells called Oligodendrocyte - which ensheath the Axon of Neurons in the Central Nervous System, in a fatty substance called Myelin in the Peripheral nervous system. The Oligodendrocytes are called Schwann cell. Antibodies signal Macrophage to come and eat the myelin as if it was an invading pathogen or dead tissue. The Oligodendrocytes/Schwanns try to regenerate the myelin (as in Relapsing/Remitting MS) but can't keep up (as in Progressive MS).

LSD has its impact on inhibitory and stimulatory neurons which keep the senses separated, causing its euphoria and effect of Synesthesia. About the only physical injury one can get from LSD is doing something stupid while "tripping" (which can present multiple opportunities for such accidental self-injury). LSD doesn't impact the immune system, so it would not cause or impact MS.

https://www.quora.com/Do-recreational-drugs-like-LSD-affect-Multiple-Sclerosis-attacks​

 

[mr peabody]

I was recently introduced to an alternative health care clinic in Mexico. I was shocked to find out they've treated over 750 patients suffering from MS using ibogaine!

I spoke with a 43 year old women who takes ibogaine immediately after feeling the onset of an attack. She says it stops her relapses dead in their tracks, and she's taken ibogaine at least once a year for the last 22 years. Another man claims to have thrown his wheel chair in the garbage after his first time using 5-MEO-DMT. He says the trip taught him a new way to use his legs.

Again.. 750+ patients have used this, just in this one clinic in Mexico.

The clinic's chief of staff says he's used COCKTAILS of several different psychedelic medicines for treating of not just multiple sclerosis, but on a myriad of neurological diseases with great results. They regularly use ibogaine, DMT, ayahuasca, peyote, magic mushrooms, and occasionally LSD.

-WarmOutToday

http://www.thisisms.com/forum/natura...opic24133.html​

 

[mr peabody]

T helper cells bearing the CXCR6 surface marker drive multiple sclerosis by producing a host of proteins
that damage nerve fibers by attacking their protective myelin sheath. The cells are shown here releasing
GM-CSF, which stimulates other immune cells to release damaging inflammatory compounds.

Antibody found to prevent and reverse MS in mice*

Neuroscience News | Oct 4 2019

Multiple sclerosis, an autoimmune disorder, is known to be driven by “helper” T cells - white blood cells that mount an inflammatory attack on the brain and spinal cord. A new study pinpoints the specific subgroup of helper T cells that cause MS, as well as a protein on their surface, called CXCR6, that marks them. An antibody targeting CXCR6 both prevented and reversed MS in a mouse model, researchers reported this week.

If the findings bear out in human studies, targeting these rogue T cells could ameliorate MS. The findings could also apply to other forms of autoimmune encephalomyelitis (inflammation of the brain and spinal cord), as well as inflammatory arthritis, says Eileen Remold-O’Donnell, PhD, of the Program in Cellular and Molecular Medicine at Boston Children’s Hospital, senior author on the paper.

Remold-O’Donnell and Lifei Hou, PhD, her former postdoctoral fellow and first author on the paper, have filed a patent covering the work and have formed a company, Edelweiss Immune, Inc., in which they have equity ownership together with Boston Children’s Hospital.

“We’ve demonstrated in mice you can target these cells and get rid of them,” says Remold-O’Donnell, a principal in the company together with Hou. “We don’t know if this approach would be appropriate for all cases of MS, but it could be effective in the early inflammatory stages of the disease.”

Targeting MS-inducing cells

T helper cells, in general, have been known to drive MS, coordinating the attack on the protective myelin sheath that covers nerve fibers. But there are many different types of T helper cells. Recent studies have pointed to TH17 cells, but some TH17 cells appear not to be involved in MS.

The new study zeroed in on a subset of TH17-derived cells, all bearing the CXCR6 marker. These cells are fast-proliferating and very damaging, producing one set of proteins that directly damage cells and others, including GM-CSF, that stimulate an inflammatory attack by other immune cells known as macrophages.

The study showed that these cells also produce increased amounts of a protein called SerpinB1 (Sb1), and that this protein’s presence is necessary for MS symptoms. When Sb1 was genetically deleted in T cells in the mouse MS model, fewer immune cells survived to infiltrate the spinal cord, and the disease was ameliorated as compared with control mice. The team then went on to show that these Sb1-containing cells could be readily identified with antibodies targeting the CXCR6 surface protein.

Human counterparts

To investigate whether CXCR6-positive cells are relevant in human disease, Remold-O’Donnell and Hou worked with physicians in Boston Children’s departments of Immunology and Neurology, as well as rheumatologists at Brigham and Women’s Hospital, to obtain samples of synovial fluid (from the cavities of joints) from patients with inflammatory autoimmune arthritis. They indeed found elevated levels of CXCR6+ cells in the inflamed joints. In contrast, circulating blood from the arthritis patients did not have elevated CXCR6+ cells. Nor did the blood of patients with MS or from healthy controls.

When the team used monoclonal antibodies to target CXCR6, the harmful cells largely disappeared, and mice, which were primed to get MS, did not develop the disease.

The researchers believe treatments to deplete CXCR6+ cells could mitigate MS and possibly other autoimmune disorders while largely leaving other T cell immune defenses intact. The new company, Edelweiss Immune, will be carrying the research forward.

“Many drugs have been developed to treat autoimmune diseases, such as glucocorticoids and cytotoxic reagents,” says Hou. “However, none selectively target pathogenic T cells, and long-term use of immunosuppressive agents results in broad immunosuppression and compromised immune defenses. Therapeutics with better selectivity, safety, and efficacy are needed.”

*From the article here :

Targeting certain rogue T cells prevents and reverses multiple sclerosis: Mouse study - Neuroscience News

TH17 cells produced increased amounts of SerpinB1, a protein implicated in multiple sclerosis symptoms. SerpinB1 cells were identified with antibodies targeting the CXCR6 surface protein. Using monoclonal antibodies to target CXCR6, the cells disappeared significantly, and the mice primed to...

neurosciencenews.com

 

[mr peabody]

Many MS patients considering stem cell transplantation

Medical Xpress | Nov 8 2019

Many multiple sclerosis (MS) patients are considering autologous hematopoietic stem cell transplantation (aHSCT) as a treatment option, according to a study published in the January 2020 issue of Multiple Sclerosis and Related Disorders.

Floriaan G.C.M. De Kleermaeker, from the Viecuri Medical Center in Venlo, Netherlands, and colleagues conducted a survey of 137 patients with MS to assess disease history, knowledge about aHSCT, expectations of aHSCT, information sources, and the role they assign to their neurologists.

The researchers found that 54 percent of patients are considering aHSCT either now or in the future. Consideration was higher in those who are dissatisfied with current treatment, have a shorter disease duration (≤10 years), or are more disabled (Expanded Disability Status Scale >3.5). Only one in four reported having sufficient knowledge about aHSCT. Although patients prefer receiving information from their neurologist, patients mainly use potentially unreliable information sources (e.g., the internet and television). Half of patients think aHSCT is superior to highly effective disease-modifying therapy. Among patients interested in aHSCT, expectations of efficacy are significantly higher versus patients not wanting to undergo aHSCT. Only about one in three patients can cite at least one side effect.

"Neurologists should proactively inform their patients about the potential benefits and risks of aHSCT to enable them to choose the best treatment option," the authors write.

Many multiple sclerosis patients considering stem cell transplant

(HealthDay)—Many multiple sclerosis (MS) patients are considering autologous hematopoietic stem cell transplantation (aHSCT) as a treatment option, according to a study published in the January 2020 issue of Multiple Sclerosis and Related Disorders.

medicalxpress.com

 

[mr peabody]

Scientific breakthrough provides new hope for millions living with MS

Neuroscience News | April 18, 2019

Researchers at Oregon Health & Science University have developed a compound that stimulates repair of the protective sheath that covers nerve cells in the brain and spinal cord.

MS is a chronic condition that affects an estimated 2.3 million people worldwide. In MS, the sheath covering nerve fibers in the brain and spinal cord becomes damaged, slowing or blocking electrical signals from reaching the eyes, muscles and other parts of the body. This sheath is called myelin. Although myelin can regrow through exposure to thyroid hormones, researchers have not pursued thyroid hormone therapies due to unacceptable side effects.

Although several treatments and medications alleviate the symptoms of MS, there is no cure.

“There are no drugs available today that will re-myelinate the de-myelinated axons and nerve fibers, and ours does that,” said senior author Tom Scanlan, Ph.D., professor of physiology and pharmacology in the OHSU School of Medicine.

Co-author Dennis Bourdette, M.D., chair of neurology in the OHSU School of Medicine and director of the OHSU Multiple Sclerosis Center, said he expects it will be a few years before the compound advances to the stage of a clinical trial involving people. Yet the study provides fresh hope for patients in Oregon and beyond.

“It could have a significant impact on patients debilitated by MS,” Bourdette said.

The discovery, if ultimately proven in clinical trials involving people, appears to accomplish two important goals:

- Myelin repair with minimal side effects: The study demonstrated that the compound – known as sobetirome – promotes remylenation without the severe side effects of thyroid hormone therapy. Thyroid hormone therapy has not been tried in people because chronic elevated exposure known as hyperthyroidism harms the heart, bone, and skeletal muscle.

- Efficient delivery: Researchers developed a new derivative of sobetirome (Sob-AM2) that penetrates the blood brain barrier, enabling a tenfold increase in infiltration to the central nervous system.

“We’re taking advantage of the endogenous ability of thyroid hormone to repair myelin without the side effects,” said lead author Meredith Hartley, Ph.D., an OHSU postdoctoral researcher in physiology and pharmacology.

Co-authors credited the breakthrough to a collaboration that involved scientists and physicians with expertise ranging across neurology, genetics, advanced imaging, physiology and pharmacology.

One patient said the research could be a “total game-changer” for people with MS.

Laura Wieden, 48, has lived with multiple sclerosis since being diagnosed in 1995. The daughter of Portland advertising executive Dan Wieden, she is the namesake and board member of the Laura Fund for Innovation in Multiple Sclerosis, which funded much of the research involved in the study published today.

“I am really optimistic,” Wieden said. “I hope that this will be a missing link that could just change the lives of people with MS.”

Scanlan originally developed sobetirome as a synthetic molecule more than two decades ago, initially with an eye toward using it to lower cholesterol. In recent years, Scanlan’s lab adapted it as a promising treatment for a rare metabolic disease called adrenoleukodystrophy, or ALD.

Six years ago, Bourdette suggested trying the compound to repair myelin in MS.

Supported by funding provided through the Laura Fund and the National Multiple Sclerosis Society, the team turned to Ben Emery, Ph.D., an associate professor of neurology in the OHSU School of Medicine. Emery, an expert who previously established his own lab in Australia focused on the molecular basis of myelination, genetically engineered a mouse model to test the treatment.

With promising early results, researchers wanted to see if they could increase the amount of sobetirome that penetrated into the central nervous system.

They did so through a clever trick of chemistry known as a prodrug strategy.

Scientists added a chemical tag to the original sobetirome molecule, creating an inert compound called Sob-AM2. The tag’s main purpose is to eliminate a negative charge that prevents sobetirome from efficiently penetrating the blood-brain barrier. Once Sob-AM2 slips past the barrier and reaches the brain, it encounters a particular type of brain enzyme that cleaves the tag and converts Sob-AM2 back into sobetirome.

“It’s a Trojan horse type of thing,” Scanlan said.

Researchers found that the treatment in mice not only triggered myelin repair, but they also measured substantial motor improvements in mice treated with the compound.

“The mouse showed close to a full recovery,” Scanlan said.

Scientists say they are confident that the compound will translate from mice to people. To that end, OHSU has licensed the technology to Llama Therapeutics Inc., a biotechnology company in San Carlos, California. Llama is working to advance these molecules toward human clinical trials in MS and other diseases.

Bourdette said even though it may not help his patients today, he’s optimistic the discovery eventually will move from the lab into the clinic.

“Right now, what it means is hope,” he said.

Study shows promise in repairing damaged myelin

Summary: A study in mouse models of multiple sclerosis demonstrates a compound called sobetirome promotes remyelination, and a derivative of the compound can penetrate the blood-brain barrier to enabl

neurosciencenews.com

 

[mr peabody]

Slowing the progression of MS

University of Montreal | Medical Xpress | Nov 13, 2019

Over 77,000 Canadians are living with multiple sclerosis, a disease whose causes still remain unknown. Presently, they have no hope for a cure. In a study published in Science Translational Medicine, researchers at the University of Montreal Hospital Research Centre (CRCHUM) identify a molecule named ALCAM which, once blocked, delays the progression of the disease. Their results, obtained from in vitro human and in vivo mouse studies, could lead to the development of a new generation of therapies to treat this autoimmune disease.

Under normal conditions, the blood-brain barrier protects our brain from exposure to harmful elements. For example, it prevents cells of the immune system such as lymphocytes from invading our central nervous system. However, in people with multiple sclerosis, this barrier is permeable. A large number of lymphocytes manage to migrate into the brain and deteriorate its tissues (by destruction of the myelin sheath that protects the neurons and enables the transmission of nerve impulses).

"In our study, we show for the first time that a molecule called ALCAM (Activated Leukocyte Cell Adhesion Molecule), expressed by B cells, controls their entry into the brain via blood vessels. It allows them to migrate to the other side of the blood-brain barrier in mice and humans. By blocking this molecule in mice, we were able to reduce the flow of B cells into their brains and, as a result, slow the progression of the disease," said Dr. Alexandre Prat, a researcher at the CRCHUM, professor at the Université de Montréal and holder of the Canada Research Chair in Multiple Sclerosis.

In the animal model of multiple sclerosis, the administration of an antibody that blocks ALCAM impairs the capacity of B lymphocytes to infiltrate the brain and spinal cord. B cells contribute to the progressive phase of multiple sclerosis. Certain medications, commonly known as anti-B-cell drugs, reduce its progression and the resulting disability.

"The molecule ALCAM is expressed at higher levels on the B cells of people with multiple sclerosis. By specifically targeting this molecule, we will now be able to explore other therapeutic avenues for the treatment of this disease," said Dr. Prat.

Multiple sclerosis can cause symptoms such as fatigue, lack of coordination, vision problems, cognitive impairment and mood changes. One in every 385 Canadians have the disease, including 20,000 people in Quebec. Sixty per cent of adults with multiple sclerosis are between the ages of 20 and 49 and women are three times more likely than men to be diagnosed with it.

Slowing the progression of multiple sclerosis

Over 77,000 Canadians are living with multiple sclerosis, a disease whose causes still remain unknown. Presently, they have no hope for a cure. In a study published in Science Translational Medicine, researchers at the University of Montreal Hospital Research Centre (CRCHUM) identify a molecule...

medicalxpress.com

 

[mr peabody]

Can naltrexone help treat MS?

by Alan Carter, Pharm.D. | Medical News Today | Jun 12 2019

Naltrexone, in low doses, has recently become a popular drug for treating multiple sclerosis. This is an off-label use, and research into its effectiveness is still underway.

Multiple sclerosis (MS) is a disease that damages the nerve cells. As it progresses, symptoms can get in the way of daily life and impair movement, speech, and other bodily functions. There is no cure, but there are treatments people can use to manage the symptoms and slow down the disease progression.

Naltrexone is one emerging treatment option. Naltrexone is a drug officially approved to treat alcohol and opioid addictions. In lower doses, doctors have started using the drug to help manage MS.

In this article, we look at the current research into naltrexone, how doctors use it to treat MS symptoms, its side effects, and warnings.

What is naltrexone?

The Food and Drug Administration (FDA)Trusted Source have approved naltrexone for treating alcohol dependence and preventing a relapse from opioid dependence. The drug prevents people from feeling the high they associate with these substances.

In lower doses, doctors are also using naltrexone to treat a variety of conditions, including MS.

Using naltrexone to treat MS is considered off-label use. This means that though it may be effective, researchers have not thoroughly studied its effectiveness, and the FDA have not approved it for treating MS.

Naltrexone and MS

Low-dose naltrexone causes the body to release endorphins over an extended period. Endorphins are hormones that the body usually releases during stress or pain. They interact with the opiate receptors in the brain, which helps reduce the feelings of pain.

Naltrexone may work for MS because endorphins help reduce inflammation. Inflammation is the underlying cause of MS symptoms.

Some anecdotal evidence supports using low-dose naltrexone for treating MS symptoms. This evidence is primarily from people who report noticing a reduction in symptoms after taking naltrexone.

However, clinical evidence is lacking, and what does exist appears to point out that naltrexone may not do much for people living with MS.

For example, a study published in 2017Trusted Source looked at whether people taking naltrexone for MS reduced their use of other medications. This would suggest that naltrexone was working. However, the study found that few people reduced their use of other medications.

Researchers found similar results in another study. They collected 10 years of clinical data and lab reports specifically looking at people who used naltrexone. They found that naltrexone is generally safe but likely does not have a significant effect on treating MS symptoms.

Still, doctors need more research to understand the effects of naltrexone on MS symptoms better. Specifically, studies need to look at the direct use of low-dose naltrexone to treat MS symptoms.

Is naltrexone safe?

Low-dose naltrexone appears to be generally safe for people with MS. Research has not shown serious side effects. And though evidence may be lacking to suggest it will help greatly, there is also no evidence that suggests naltrexone is dangerous.

However, a person taking naltrexone should know about potential side effects that this article highlights below.

Side effects and risks

Warnings, side effects, and risks for naltrexone apply to higher doses. Lower doses may be safer, but this is not a guarantee.

As with any medication, there are certain risks that people associate with the full dose of naltrexone. One of the primary risks is the potential for long-lasting liver damage.

Naltrexone can also lead to the development of thrombocytopenia. Thrombocytopenia is a condition that causes uncontrollable bleeding or increased bruising.

Common side effects of full-dose naltrexone include:

- constipation
- depression
- insomnia
- nausea and vomiting
- fatigue
- anxiety
- abdominal pain
- dizziness
- decreased appetite
- headache

A person should not take naltrexone without a doctor's recommendation if they are:

- taking opioid medications
- in acute opiate withdrawal
- in an opioid maintenance program
- dealing with liver problems

Finally, people should not take medications without first discussing them with a doctor.

People should also avoid splitting higher dose pills on their own. Instead, they should talk to their doctor about getting a prescription for a lower dose of naltrexone.

Summary

Naltrexone for MS symptoms is not well studied or proven.

Some people have reported that it works well in controlling their MS symptoms, but what studies exist indicate it has limited, if any, effect on MS symptoms.

People should discuss using naltrexone with their doctor before trying to use it on their own.

Naltrexone for MS: What it does and side effects

Low doses of naltrexone are a recent, popular treatment for MS symptoms. In this article, we look at the research, action, and side effects of naltrexone for MS.

www.medicalnewstoday.com

 

[mr peabody]

Herpes is a risk factor for developing MS*

by Katarina Zimmer | The Scientist | Jan 10 2020

A study of 16,000 people suggests that human herpesvirus 6A is a risk factor for developing multiple sclerosis, reinvigorating a neglected hypothesis that the virus could be involved in triggering the disease.

As early as the 1990s, researchers proposed that a very common type of herpes virus—then known as human herpesvirus 6 (HHV6)—could be somehow involved in the development of multiple sclerosis, a neurodegenerative disease characterized by autoimmune reactions against the protective myelin coating of the central nervous system.

However, the association between HHV6 and the disease soon became fraught with controversy as further studies produced discordant results. Complicating matters further, HHV6 turned out to be two related, but distinct variants—HHV6A and HHV6B. Because the two viruses are similar, for a while no method existed to tell whether a patient had been infected with one or the other, or both—making it difficult to draw a definitive association between either of the viruses and the disease.

Now, a collaboration of European researchers has developed a technique capable of distinguishing antibodies against one variant from the other. Using that method in a Swedish cohort of more than 8,700 multiple sclerosis patients and more than 7,200 controls, they found that patients were much more likely to carry higher levels of anti-HHV6A antibodies than healthy people, while they were likelier to carry fewer antibodies against HHV6B. The findings, published last November in Frontiers in Immunology, hint that previous contradictory results may at least be partially explained by the fact that researchers couldn’t distinguish between the two viruses.

“This article now makes a pretty convincing case that it is HHV6A that correlates with multiple sclerosis, and not HHV6B,” remarks Margot Mayer-Pröschel, a neuroscientist at the University of Rochester Medical Center. “Researchers can now focus on one of these viruses rather than looking at both of them together.”

HHV6A and HHV6B are two of eight herpesviruses known to infect people. More is known about the HHV6B variant, which most people catch as infants. It causes a brief rash-fever illness known as Roseola. Both viruses typically fall dormant after the initial infection, sometimes re-activating later in life. Luckily for researchers, antibodies against them linger in the blood well into adulthood.

Through a careful analysis of the two viruses, researchers at the German Cancer Research Center in Heidelberg were able to identify a particular protein—known as immediate-early protein 1 (IE1)—that differed between the two variants.

Along with other research groups, they turned to a cohort of 8,742 Swedish multiple sclerosis patients who were enrolled in long-term studies of the disease and whose blood serum had been collected at the Karolinska Institute. They measured serum concentrations of antibodies for the IE1 protein, and then compared them with antibody concentrations in a cohort of 7,215 healthy, age-matched control individuals. Their analysis revealed that a positive association between HHV6A antibody concentrations and multiple sclerosis, whereas there was a negative association between HHV6B antibody levels and the disease.

The team also examined the relationship between the HHV6A antibody concentrations and other known risk factors for multiple sclerosis, including the presence of antibodies against another herpesvirus called Epstein-Barr virus (EBV). Interestingly, individuals who carried high levels of antibodies against both EBV and HHV6A were more even more likely to have been diagnosed with multiple sclerosis than those who carried high levels of anti-HHV6A antibodies alone, suggesting a possible interplay between the two pathogens. The team also found a relationship with known genetic risk factors for the disease.

“It seems like there is an interaction with the other risk factors,” says coauthor Anna Fogdell-Hahn, a neuroimmunologist at the Karolinska Institute’s Center for Molecular Medicine. To her, the findings bolster the notion that it is a confluence of multiple factors that leads to the disease, and that HHV6A might be one of them.

HHV6A activity as a cause or consequence of MS?

How HHV6A might trigger or contribute to the disease is unclear, but Fogdell-Hahn has some theories she’s planning on exploring in future research. While both HHV6A and HHV6B infect neurons, HHV6A differs in that it infects oligodendrocytes, the cells that generate the protective myelin sheath around neurons and are thought to be targeted by the autoimmune reactions of multiple sclerosis. "When HHV6A reactivates and proliferates, it could borrow particular proteins from its oligodendrocyte host cells," Fogdell-Hahn speculates. "And when certain immune cells then catch the pathogen and present the virus’ proteins to other immune cells, they might mistakenly present the body’s own oligodendrocyte proteins, and thereby trigger autoimmune reactions," she says.

"Treatments exist for multiple sclerosis, but they all work by suppressing the immune system, leaving patients more vulnerable to other infections," Fogdell-Hahn notes. “We should not give up the ambition to try to really understand what starts the disease,” she says.

Steven Jacobson, the chief of the viral immunology section at the National Institute of Neurological Disorders and Stroke, who has collaborated with Fogdell-Hahn in the past but wasn’t involved in the current study, is impressed by the sheer size of the study, which gives the findings statistical power. “Very few of us have done studies in 15,000 . . . individuals. That to me is a real strength,” he says. "Without such large numbers, it’s difficult to uncover firm associations between relatively rare diseases and viruses that nearly everyone carries."

One important question, he notes, is whether HHV6A is simply reactivated as a result of the inflammatory symptoms of multiple sclerosis, rather than a contributor to the disease. To Mayer-Pröschel, some of the team’s results hint at a contributing role. In a separate analysis based on a different cohort of patients whose blood samples had been taken before they developed the disease, the researchers found higher concentrations of anti-HHV6A antibodies compared to control individuals who never developed the disease. If reactivation of HHV6A were a mere consequence of the disease, one would expect patients at the most advanced stages to have the highest antibody response. However, “it was exactly opposite: the youngest patients who had not yet developed the pathology had a very robust HHV6A-specific antibody response. I thought that was enlightening,” says Mayer-Pröschel.

"Still, one would need an interventional study to prove a causative role for the virus," Jacobson says—"for instance by blocking the virus and investigating whether the patients’ symptoms improve. But that’s easier said than done," he notes. “There are really not very great antiviral drugs out there, and it’s almost a catch 22 situation where you need the antiviral drug to show this effect on the disease, but until you show that the virus has something to do with the disease, no one is going to make the antiviral drug.” "Nevertheless, the new research is a step in the right direction," he notes.

"The biggest effect of the study," Mayer-Pröschel says, "is that it may attract further funding to studying HHV6A—a field some say has been largely neglected by funding bodies." Fogdell-Hahn agrees. “I hope we've renewed interest in this virus,” she says. “There’s so many things that we want to do.”

Type of Herpes Virus Tied to Multiple Sclerosis

A study of 16,000 people suggests that human herpesvirus 6A is a risk factor for developing multiple sclerosis, reinvigorating a neglected hypothesis that the virus could be involved in triggering the disease.

www.the-scientist.com

 

[mr peabody]

New research suggests that a compound found in the peels of fruits such as apples, prunes, and
some herbs, can reduce further damage to neurons, and also help rebuild the protective sheaths
covering neurons, reversing the damage.

Compound in fruit peels halts damage and spurs neuronal repair in MS

Thomas Jefferson University | Neuroscience News | 6 April 2020

Study reveals ursolic acid suppresses TH17 cells, which are one of the main drivers in the pathological autoimmune response of MS.

Ursolic acid, a compound abundant in fruit peels and some herbs, appears to decrease further neural damage and help regenerate myelin in mouse models of multiple sclerosis. Study reveals ursolic acid suppresses TH17 cells, which are one of the main drivers in the pathological autoimmune response of MS.

Multiple sclerosis (MS), characterized by increasing muscle weakness and paralysis, has a number of treatments that help stall progression of the disease when used early on in the disease. But the current treatments can hardly reverse damage that has already occurred in brain cells called neurons. New research suggests that a compound found in the peels of fruits such as apples and prunes, and some herbs, can reduce further damage to neurons, and also help rebuild the protective sheaths covering neurons, reversing the damage.

“Although the evidence is preliminary – our data is from animal models of disease – it’s encouraging to see a compound that both halts and repairs damage in MS, in the lab,” says Guang-Xian Zhang, PhD, co-senior author and Professor of Neuroscience at the Sidney Kimmel Medical College at Thomas Jefferson University. The study was published in the Proceedings of the National Academy of Sciences (PNAS) on Monday April 6th.

“There is additional work we must do to test the safety of this compound, ursolic acid” says co-senior author A.M. Rostami, MD, PhD, chair of the department of Neurology at the Vickie and Jack Farber Institute for Neuroscience – Jefferson Health. “But this is a great new lead for disease treatment.”

The researchers used a lab-grade purified form of ursolic acid in mice that had established MS disease. “Many experiments have looked at mice in the acute phase, when disease is just starting or at the peak,” says Dr. Zhang. “Instead, we tested whether this compound was effective in chronic disease, once there has already been chronic damage to tissues of central nervous system.”

Drs. Zhang, Rostami, together with first author Yuan Zhang and colleagues used an established mouse model of multiple sclerosis that develops the disease slowly over the course of its life, mimicking human disease. At about day 12, the mouse begins the acute phase of the disease, when signs of MS, partial paralysis, appear, and when currently-available medications are most effective. The researchers, however, started treating mice at day 60, – a far more advanced stage of the disease when chronic tissue damage has been formed in brain and spinal cords, which needs to be repaired and regenerated.

Researchers treated the mice for 60 days, and began to see an improvement at day 20 of treatment. The mice which were paralyzed at the start of the experiment, regained the ability to walk around again, although with weakness, after treatment.

“It’s not a cure, but if we see a similar response in people, it would represent a significant change in quality of life. And most significantly, it’s a reversal, which we really haven’t seen before with other agents at such a late stage of disease,” says Dr. Zhang.

The researchers also investigated just how ursolic acid acted on cells. They observed that it suppressed Th17 cells – a type of immune cell that is one of the main drivers of the pathological autoimmune response in MS. Many currently active therapies appear to suppress Th17. But the Jefferson researchers showed that the compound could activate precursor cells to mature into much needed myelin-sheath-making cells, called oligodendrocytes.

“This maturation effect is the most crucial,” says Dr. Zhang. “Myelin-sheath-making oligodendrocytes are depleted in MS. And the stem cells that produce new oligodentrocytes are dormant and unable to mature. This compound helps activate those stem cells into making new oligodendrocytes, and is likely responsible for the reversal of symptoms we saw.”

The next steps for the investigators include testing the compound for safety. Although ursolic acid is available as a dietary supplement, it could be toxic at high doses. “There are still a number of tests to complete before the first clinical trials,” says Dr. Rostami. “However, we are moving quickly with this promising approach.”

Compound in fruit peels halts damage and spurs neuronal repair in multiple sclerosis - Neuroscience News

Ursolic acid, a compound abundant in fruit peels and some herbs, appears to decrease further neural damage and help regenerate myelin in mouse models of multiple sclerosis. Study reveals ursolic acid suppresses TH17 cells, which are one of the main drivers in the pathological autoimmune response...

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Alexander Mildner controls sorted monocytes under the microscope.

New therapeutic options for Multiple Sclerosis in sight

by Max Delbrück Center | Molecular Medicine | 20 April 2020

Multiple sclerosis (MS) is known as "the disease with a thousand faces" because symptoms and progression can vary dramatically from patient to patient. But every MS patient has one thing in common: Cells of their body's own immune system migrate to the brain, where they destroy the myelin sheath—the protective outer layer of the nerve fibers. As a result, an electrical short circuit occurs, preventing the nerve signals from being transmitted properly.

Many MS medications impair immune memory

Researchers don't yet know exactly which immune cells are involved in stripping away the myelin sheath. Autoreactive T and B cells, which wrongly identify the myelin sheath as a foreign body, travel to the brain and initiate the disease. "Up until now, MS drugs have essentially targeted these T and B cells, both of which are part of the acquired immune system," says Dr. Alexander Mildner, a scientist at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and the senior author of the paper now published in Nature Immunology.

Mildner is currently conducting externally funded research as a DFG Heisenberg fellow in Professor Achim Leutz's lab at the MDC, which focuses on cell differentiation and tumorigenesis. "But by attacking the acquired immune system, the MS drugs adversely affect the body's immune memory, thus making patients more susceptible to infections in the long run," the scientist says.

MS symptoms improved in mice by reducing monocytes

As a result, Mildner has been pursuing a different strategy for a couple of years now. He wants to find out what role immune cells—particularly those that are part of innate immunity—play in the development of MS and whether they represent a promising target structure for therapy of MS patients. "In an earlier study with a mouse model of MS, we were able to show that disease symptoms in the mice declined significantly within a few days after their monocytes were selectively destroyed by antibodies," the researcher reports. This result came as a big surprise to him and to many of his colleagues. "Apparently, it is not only T and B cells that are involved in causing tissue damage in MS," Mildner says.

The monocytes he studied are a special type of white blood cells that shortly circulate in the blood before migrating into tissue. Once there, they transform themselves into effector cells (phagocytes) and destroy foreign tissue in the central nervous system (CNS) - or which, during MS, they wrongly identify as such. "This process," Mildner says, "leads to inflammation and tissue damage in the brain."

n the current study published in Nature Immunology, which he conducted in collaboration with an Israeli team led by Professor Ido Amit from the Department of Immunology at the Weizmann Institute of Science, Mildner and his team also focused on monocytes. "In recent years, we realized that several types of these immune cells exist, which might carry out different functions," the researcher says. "We therefore wanted to examine in our mouse model of MS the monocytes in greater detail using single-cell sequencing and to find out, which monocyte subsets are present in the brain in MS and are responsible for tissue damage."

He and his colleagues identified six monocyte subtypes, four of which were previously unknown. As in his earlier study, Mildner injected the mice with antibodies against a specific monocyte surface protein. As expected, the cells died and the MS symptoms in the mice decreased within a short period of time. "But what surprised us was that the antibodies did not destroy all monocyte subsets in the brain that have this surface protein," Mildner says.

Not all monocytes destroy the protective myelin sheath

"Only a certain type of monocyte, the Cxcl10+ cells, was destroyed by the antibody treatment," Mildner says. "These are apparently the cells that are primarily responsible for causing MS tissue damage in the brain."

With the help of single-cell sequencing, he and his team also discovered that this cell type differs from other monocytes in two essential ways: First, Cxcl10+ cells have a particularly large number of receptors for a signal protein secreted by T cells that induces tissue damaging properties in monocytes. Second, these cells produce large amounts of interleukin-1-beta, a substance that opens the blood-brain barrier, enabling immune cells to more easily pass from the blood to the brain and exacerbate the symptoms. "Our research suggests that T cells, as disease initiators, travel to the CNS in order to lure there the monocytes that are responsible for the primary tissue damage," Mildner explains.

The other monocyte subsets that were identified, he speculates, are perhaps even involved in repair processes in which the body tries to rebuild the damaged myelin. In light of the study's findings, he thinks it is also possible that the T and B cells are not even directly involved in stripping away the myelin sheath, but only indirectly in that they prompt the Cxcl10+ monocytes to attack the protective layer of the axons.

Many side effects may be preventable

"If that is the case, in the future, most forms of MS could be treated by specifically deactivating the Cxcl10+ monocytes instead of targeting the T or B cells of the immune system," Mildner says. "This would protect the body's immune memory and prevent many side effects of current MS therapies." The researcher and his team next plan to investigate whether the Cxcl10+ monocytes are also present outside the CNS. "If they exist in the body's periphery, for example, in the lymph nodes," he says, "there they would be easier to target with therapeutics than in the brain."

New therapeutic options for multiple sclerosis in sight

Multiple sclerosis (MS) is known as "the disease with a thousand faces" because symptoms and progression can vary dramatically from patient to patient. But every MS patient has one thing in common: Cells of their body's own immune system migrate to the brain, where they destroy the myelin...

medicalxpress.com

 

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Demyelination by MS. The CD68 colored tissue shows several macrophages in the area of the lesion.

Animal study shows transplanted human brain cells repair MS damage

by University of Rochester Medical Center | Medical Xpress | 19 May 2020

A new study shows that when specific human brain cells are transplanted into animal models of multiple sclerosis, the cells repair damage and restore function.

"These findings demonstrate that through the transplantation of human glial cells, we can effectively achieve remyelination in the adult brain," Steve Goldman, M.D., Ph.D., professor of Neurology and Neuroscience at the University of Rochester Medical Center (URMC), co-director of the Center for Translational Neuromedicine, and lead author of the study. "These findings have significant therapeutics implications and represent a proof-of-concept for future clinical trials for multiple sclerosis and potential other neurodegenerative diseases."

The findings, which appear in the journal Cell Reports, are the culmination of more than 15 years of research at URMC understanding support cells found in the brain called glia, how the cells develop and function, and their role in neurological disorders.

Goldman's lab has developed techniques to manipulate the chemical signaling of embryonic and induced pluripotent stem cells to create glia. A subtype of these, called glial progenitor cells, gives rise to the brain's main support cells, astrocytes and oligodendrocytes, which play important roles in the health and signaling function of nerve cells.

In multiple sclerosis, an autoimmune disorder, glial cells are lost during the course of the disease. Specifically, the immune system attacks oligodendrocytes. These cells make a substance called myelin, which, in turn, produce the "insulation" that allow neighboring nerve cells to communicate with one another.

As myelin is lost during disease, signals between nerve cells becomes disrupted, which results in the loss of function reflected in the sensory, motor, and cognitive deficits. In the early stages of the disease, referred to as relapsing multiple sclerosis, the lost myelin is replenished by oligodendrocytes. However, over time these cells become exhausted, can no longer serve this function, and the disease becomes progressive and irreversible.

In the new study, Goldman's lab showed that when human glia progenitor cells are transplanted into adult mouse models of progressive multiple sclerosis, the cells migrated to where needed in the brain, created new oligodendrocytes, and replaced the lost myelin. The study also showed that this process of remyelination restored motor function in the mice. The researchers believe this approach could also be applied to other neurological disorders, such as pediatric leukodystrophies—childhood hereditary diseases in which myelin fails to develop—and certain types of stroke affecting the white matter in adults.

This research is in the process of being developed by a University of Rochester start-up company Oscine Therapeutics. The company's experimental transplant therapy for multiple sclerosis and other glial diseases, such as Huntington's disease, is currently under early FDA review for clinical trials. Goldman is the scientific founder, an officer, and holds equity in the company.

The study provides one of the final pieces of scientific evidence necessary to advance this treatment strategy to clinical trials.

Animal study shows human brain cells repair damage in multiple sclerosis

A new study shows that when specific human brain cells are transplanted into animal models of multiple sclerosis and other white matter diseases, the cells repair damage and restore function. The study provides one of the final pieces of scientific evidence necessary to advance this treatment...

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Patients report that cannabis eases spasticity in Multiple Sclerosis

HealthDay | Medical Xpress | 28 Feb 2020

Cannabis use is common among multiple sclerosis (MS) patients with spasticity, according to a research letter published online Feb. 11 in Multiple Sclerosis and Related Disorders.

Jessica Rice, M.D., from the Oregon Health and Science University in Portland, and colleagues characterized cannabis use among patients (=18 years of age) with MS and self-reported lower-extremity spasticity.

The researchers found that 54 percent of patients reported ever using cannabis and 36 percent reported current use. Of those who used cannabis, 79 percent reported multiple routes of administration, and 58 percent reported at least daily use. More than three-quarters of patients (79 percent) reported finding cannabis helpful for spasticity. Just over one-quarter (26 percent) used cannabis and prescribed oral antispasticity medications.

"While evidence supports the benefit of certain cannabinoid formulations for improving self-reported MS-associated spasticity, these specific formulations are not available in the United States, and the products in states where cannabis is legal are heterogeneous in their purity and cannabinoid content," the authors write. "This makes it difficult to provide evidence-based recommendations to patients."

Patients report cannabis eases spasticity in multiple sclerosis

(HealthDay)—Cannabis use is common among multiple sclerosis (MS) patients with spasticity, according to a research letter published online Feb. 11 in Multiple Sclerosis and Related Disorders.

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Betaseron anti-inflammatory therapy for Multiple Sclerosis

MS News Today

Betaseron (interferon beta 1b) is an anti-inflammatory therapy for multiple sclerosis currently produced by Bayer HealthCare. It is a formulation of interferon beta 1b indicated for patients with relapsing-remitting multiple sclerosis (RRMS). In clinical trials, Betaseron was shown to reduce the number of flare-ups in patients who have had their first symptoms of MS and have signs of MS according to magnetic resonance imaging (MRI).

History of Betaseron

Multiple clinical trials have been conducted to demonstrate the safety and efficacy of Betaseron in MS patients, and studies continue to be conducted. These studies led to the original approval for Betaseron by the U.S. Food and Drug Administration in 1993.

One study used to submit Betaseron to the FDA for approval was a 2-year study in which Betaseron delayed the time to a second flare-up in patients with clinically isolated symptoms. In that study, patients started treatment soon after experiencing their first MS flare in which 292 patients were treated with Betaseron, and 176 patients were treated with placebo. Results showed a significantly reduced risk for a second flare with Betaseron treatment. The likelihood for Betaseron-treated patients to experience a flare was 28%, compared to 45 percent for placebo-treated patients.

In this same study, Betaseron also reduced the number of newly active brain lesions detectable by MRI. Among 292 Betaseron-treated patients, an average of 3.7 newly active brain lesions were detected, compared to 8.5 newly active brain lesions in placebo-treated patients. Although Betaseron reduces the time to a second flare-up and the number of newly active brain lesions, there is no current evidence to suggest that Betaseron reduces disability.

How Betaseron works

Betaseron reduces inflammation in the nervous system. As a cytokine (a protein produced by the body that can influence the immune response), Betaseron influences cells in the nervous system to produce fewer pro-inflammatory agents and more anti-inflammatory agents, thus protecting neurons from damage. It may also prevent immune cells from crossing the blood-brain barrier (BBB), stopping them from reaching the neurons in the central nervous system (CNS).

Betaseron (interferon beta 1b) for Multiple Sclerosis

Betaseron (interferon beta 1b) is an anti-inflammatory therapy for multiple sclerosis currently produced by Bayer HealthCare. It is a formulation of interferon beta 1b indicated for patients with relapsing-remitting multiple sclerosis (RRMS). In clinical trials, Betaseron was shown to reduce the...

multiplesclerosisnewstoday.com

 

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Anti-Reelin is a therapeutic approach that selectively targets the vascular barrier, blocking infiltration of inflammatory cells,
demyelination and, consequently, paralysis.

Researchers find promising new treatment approach for Multiple Sclerosis

by UT Southwestern Medical Center | Medical Xpress | 12 Aug 2020

In an animal model of multiple sclerosis (MS), decreasing the amount of a protein made in the liver significantly protected against development of the disease's characteristic symptoms and promoted recovery in symptomatic animals, UTSW scientists report.

The findings, published online today by Science Translational Medicine, could lead to a new treatment strategy for this neurological disease and other conditions marked by chronic inflammation.

In 1997, researchers discovered a protein secreted in the brain called Reelin. Subsequent work showed that Reelin appears to help the brain organize itself during development and assist in forming connections between brain cells during adulthood. However, as researchers learned more about Reelin, they discovered that large amounts of it are produced in the liver and that cells lining blood vessels have receptors for this protein.

A 2016 study by Joachim Herz, M.D., director of the Center for Translational Neurodegeneration Research and professor in the departments of molecular genetics, neurology and neurotherapeutics, and neuroscience at UTSW, and his colleagues showed that depleting levels of circulating Reelin protected mice from atherosclerosis. Probing deeper into the mechanism behind this phenomenon, they found that Reelin appears to regulate the production of adhesion molecules on blood vessel walls that capture circulating monocytes, a type of inflammation-inducing immune cell. When the scientists decreased Reelin in animal models, levels of these adhesion molecules also declined, preventing them from capturing monocytes and causing inflammation.

Wondering if Reelin plays a similar role in other inflammatory diseases, Herz, along with Laurent Calvier, Ph.D., an instructor in the department of molecular genetics at UTSW, and their colleagues investigated this protein's role in MS, a neurodegenerative disease that affects an estimated 2.3 million people worldwide. They started by examining blood concentrations of Reelin in patients with relapsing-remitting MS, the most common form of the disease. They found that while Reelin concentrations were about the same in patients in remission as those without the disease, concentrations were elevated in patients during relapse. These findings suggest that circulating Reelin levels might correlate with MS severity and stages, and that lowering Reelin levels might be a novel way to treat MS.

Investigating further, Herz, Calvier, and their colleagues worked with mice affected by a disease called experimental autoimmune encephalomyelitis (EAE), a condition that mimics human MS. When these animals were genetically modified so that the researchers could control Reelin production, they found that eliminating this protein substantially mitigated the disease's typical paralysis or even eliminated it altogether, in contrast to mice with normal Reelin levels. These effects appeared to stem from the lack of monocyte adhesion on the altered animals' blood vessel walls, which prevented entry into the central nervous system.

The researchers had further success preventing paralysis when unaltered animals with EAE received antibodies that inactivated Reelin. This strategy was even effective in animals that already displayed symptoms of the disease—a situation that more closely mimics human patients diagnosed with MS—reducing paralysis severity and promoting healing.

Herz and Calvier suggest that reducing immune cells' ability to accumulate and cause inflammation by altering Reelin levels could represent a new strategy for treating patients with MS, a disease for which several effective drugs exist that nevertheless can have significant side effects. Additionally, they say, reducing Reelin could alter the course of several other conditions marked by chronic inflammation, including psoriasis, Crohn's disease, and rheumatoid arthritis.

"We think we can use this intervention for a wide range of inflammatory diseases that have been difficult to therapeutically address," Herz says. "We are now in the process of testing this in animal models for these human diseases. In preparation for future human clinical trials, we are also working at humanizing a monoclonal antibody that can clear Reelin from human blood."

Researchers find promising new treatment approach for multiple sclerosis

In an animal model of multiple sclerosis (MS), decreasing the amount of a protein made in the liver significantly protected against development of the disease's characteristic symptoms and promoted recovery in symptomatic animals, UTSW scientists report.

medicalxpress.com

 

[mr peabody]

Remyelination in the spinal cord after experimental focal degradation of myelin sheaths, simulating a lesion caused by multiple sclerosis. In young adults,
the myelin sheath (dark rings) around axons (light gray circular structures) can be rebuilt, but this process is not fully efficient and its efficiency decreases
sharply with age and as the disease progresses.

Mechanisms identified to restore myelin sheaths in MS*

by Universitaet Mainz | Medical Xpress | 24 Aug 2020

A research team led by neurobiologist Professor Claire Jacob has identified an important mechanism that can be used to control the restoration of myelin sheaths following traumatic injury and in degenerative diseases. With the insights gained, the researchers were able to regenerate damaged myelin sheaths in mice by treating them with the active substance theophylline, thereby restoring their nerve cell function. The groundbreaking findings are the result of research carried out at Johannes Gutenberg University Mainz (JGU) and the University of Fribourg in Switzerland.

Neurons are composed of axons, i.e., long fiber-like extensions that transmit signals to other cells. Many of them are surrounded by a myelin sheath, a thick fatty layer that protects them and helps to transfer stimuli rapidly. Without myelin, the functional capacity of neurons—and therefore of the whole nervous system—is limited and neurons can easily degenerate. Multiple Sclerosis (MS) is one of the diseases associated with myelin sheath degradation. MS patients suffer successive episodes of demyelination resulting in a progressive loss of function of their nervous system. Remyelination of the axons can prevent this.

The aim is to restore the axons' protective myelin coating

Intact myelin sheaths are a prerequisite for the healthy functioning of the peripheral and central nervous systems. If the peripheral nervous system (PNS) is damaged, in an accident involving injury to the arms or legs for example, the axons and their myelin sheaths can recover relatively well. "Regeneration of the PNS is quite efficient, although it could be improved," said Professor Claire Jacob, pointing out that even young people do not experience complete regeneration.

However, the central nervous system (CNS) is completely different in this regard as there is no efficient restoration of the axons and therefore of the myelin sheath after a lesion. This means that CNS injuries usually result in permanent paralysis—as in the case of MS when loss of myelin leads to axon degeneration. MS is the most common neurodegenerative disease of the CNS and is attributable to the degradation of the myelin sheath of neurons.The occurrence of successive lesions can cause permanent loss of function of the CNS if myelin sheath restoration is inefficient. The capacity of the body to remyelinate decreases dramatically with age. "In order to promote the restoration of myelin, we need to understand the process that controls the mechanism," emphasized Jacob.

In the recent project, her research group investigated how remyelination occurs in both peripheral and central nervous systems of mice. "First, we wanted to understand the process that blocks remyelination. We subsequently studied how to counteract this blocking effect." The neuroscientists identified a protein called eEF1A1 as a key factor in the process and found that eEF1A1 activated by acetylation prevents the remyelination process, but if eEF1A1 is deactivated by deacetylation, myelin sheaths can be rebuilt. The protein that deacetylates eEF1A1 is the enzyme called histone deacetylase 2 (HDAC2).

Theophylline promotes myelin reconstruction in both peripheral and central nervous systems

"Once we understood this process, we decided to try to control it by boosting the HDAC2 activity and its synthesis in cells," said Jacob. This was achieved by using the active substance theophylline, which is also present in tea leaves and has long been used in the treatment of asthma. In a mouse model, the use of theophylline over a period of four days resulted in significant recovery. Restoration of myelin sheaths was particularly impressive in the PNS, where they recovered completely. Regeneration also improved in the CNS, as there was rapid and efficient rebuilding of myelin sheaths in both young and old mice. A low dose of the active substance was sufficient to trigger the improvements—a big plus with regard to the known side effects of theophylline, which occur at higher doses.

"In summary, this study […] shows that theophylline, by activating HDAC2, promotes eEF1A1 deacetylation, increases […] remyelination speed and efficiency after lesion of the PNS and CNS, thus appearing as a very promising compound to test in future translational studies to accelerate and promote remyelination after traumatic lesions or in the context of demyelinating disorders," write the authors in their paper published in Nature Communications. Currently, funding for corresponding clinical trials in patients is being sought, while a patent application has already been filed.

More information: Mert Duman et al. EEF1A1 deacetylation enables transcriptional activation of remyelination, Nature Communications (2020). DOI: 10.1038/s41467-020-17243-z

*From the article here :

Mechanisms identified to restore myelin sheaths after injury or in multiple sclerosis

A research team led by neurobiologist Professor Claire Jacob has identified an important mechanism that can be used to control the restoration of myelin sheaths following traumatic injury and in degenerative diseases. With the insights gained, the researchers were able to regenerate damaged...

medicalxpress.com

 

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Gut bacteria can worsen symptoms of Multiple Sclerosis*

RIKEN | Neuroscience News | 26 Aug 2020

Specific combinations of microorganisms in the gut can worsen symptoms of Multiple Sclerosis in mouse models of the autoimmune disease.

Researchers at the RIKEN Center for Integrative Medical Sciences (IMS) have discovered that a particular combination of microorganisms in the gut can worsen symptoms in a mouse model of Multiple Sclerosis. The study published in the scientific journal Nature shows that two specific gut bacteria enhance the activity of immune cells that attack the body’s own brain and spinal cord.

Multiple Sclerosis is an autoimmune disease in which the immune system attacks the myelin that covers the nerve cells of the brain and spinal cord. Demyelination affects how rapidly neurons communicate with each other and with muscles, causing a variety of symptoms including numbness, weak muscles, tremors, and the inability to walk. Gut microorganisms have been reported to affect symptoms of Multiple Sclerosis, but how bacteria in the intestines can affect myelin of the brain and spinal cord remained a mystery.

Researchers led by Hiroshi Ohno at RIKEN IMS set out find this connection using a mouse model of the disease. These mice experience similar demyelination of the spinal cord that results from autoimmune attacks by T cells that produce the cytokine IL-17A. However, giving these mice the antibiotic ampicillin reduced demyelination. The treatment also prevented the activation of a particular type of T cell. As Ohno explains, “we found that treatment with ampicillin, and only ampicillin, selectively reduced activity of T cells that attack an important protein called myelin oligodendrocyte glycoprotein [MOG], which helps myelin stick to neurons.”

This was confirmed by taking immune cells from the small intestines and other regions and measuring their cytokine production in the presence of MOG. Production was only reduced by ampicillin and only when the T cells came from the small intestine. At this point, the team knew that microorganisms in the small intestine activate MOG-specific T cells, which can then go and attack myelin. The next step was to figure out which bacteria were responsible.

Because only ampicillin reduced symptoms in the model mice, they looked for microbiota that were almost completely deleted only in ampicillin-treated mice. They found only one such bacteria, a new strain called OTU002. To test the hypothesis that OTU002 was the culprit, they examined mice that lacked all bacteria except OTU002. They found that symptoms in these mice were more severe than those in germ-free mice. At this point, the team knew that their newly discovered gut bacterium was responsible for the worsening symptoms.

Bacteria can improve or worsen MS symptoms.

“But, there was a problem,” says first author Eiji Miyauchi. “Symptoms in the OTU002-only mice were not as bad as those in the regular model mice. This means that the original effect must involve more than one microorganism.” The team hypothesized that a different bacterium was cross-reacting with MOG-specific T cells, mimicking the location on MOG that the T cells recognize. Shotgun genome sequencing revealed that a protein expressed by Lactobacillus reuteri does resemble a region of MOG, and when tested, it weakly activated MOG-specific T cells. The symptoms in mice co-colonized with L. reuteri and OTU002 were more severe than those in OTU002-only mice and were just as severe as those in the original model mice, indicating that when these two bacteria work together, the results are devastating.

“Other studies have focused on fecal microbes, or a single microbe, in patients with Multiple Sclerosis or in model mice,” says Miyauchi. “Our data emphasize the necessity of considering the synergistic effects of intestinal microbes on autoimmune diseases and give hope to people looking for effective treatments for Multiple Sclerosis.”

“But, because gut microbes and T cell binding locations on myelin differ between mouse and human, further studies using human microbes and autoreactive T cells are now needed.”

Tag Team Gut Bacteria Worsen Symptoms of Multiple Sclerosis - Neuroscience News

Specific combinations of microorganisms in the gut can worsen symptoms of multiple sclerosis in mouse models of the autoimmune disease.

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Karolinska Institutet

Study explains process that exacerbates Multiple Sclerosis

Karolinska Institute | Neuroscience News | 26 Oct 2020

Recovery from multiple sclerosis-like symptoms in mice depends upon the ability for microglia to break down the remains of damaged cells.

People with multiple sclerosis (MS) gradually develop increasing functional impairment. Researchers at Karolinska Institutet have now found a possible explanation for the progressive course of the disease in mice and how it can be reversed. The study, which is published in Science Immunology, can prove valuable to future treatments.

MS is a chronic inflammatory disease of the central nervous system (CNS) and one of the main causes of neurological functional impairment.

The disease is generally diagnosed between 20 and 30 years of age. It can cause severe neurological symptoms, such as loss of sensation and trembling, difficulties walking and maintaining balance, memory failure and visual impairment.

MS is a life-long disease with symptoms that most often gradually worsen over time.

In the majority of cases the disease comes in bouts with a certain amount of subsequent recovery. A gradual loss of function with time is, however, inevitable. Research has made great progress in treatments that reduce the frequency and damaging effects of these bouts.

“Despite these important breakthroughs, the disease generally worsens when the patient has had it for 10 to 20 years,” says Maja Jagodic, docent of experimental medicine at the Department of Clinical Neuroscience and the Centre for Molecular Medicine, Karolinska Institutet. “There is currently only one, recently approved, treatment for what is called the secondary progressive phase. The mechanisms behind this progressive phase require more research.”

Researchers at Karolinska Institutet have now shown that recovery from MS-like symptoms in mice depends on the ability of the CNS’s own immune cells – microglia – to break down the remains of damaged cells, such as myelin.

The processes was interrupted when the researchers removed a so-called autophagy gene, Atg7. Autophagy is a process where cells normally break down and recycle their own proteins and other structural components.

Without Atg7 the ability of the microglia to clean away tissue residues created by the inflammation was reduced. These residues accumulated over time, which is a possible explanation for the progressiveness of the disease.

The study also shows how microglia from aged mice resemble the cells from young mice that lacked Atg7 in terms of deficiencies in this process, which had a negative effect on the course of the disease.

This is a significant result since increasing age is an important risk factor in the progressive phase of MS.
The researchers also show how this process can be reversed.

This is a significant result since increasing age is an important risk factor in the progressive phase of MS. The researchers also show how this process can be reversed.

“The plant and fungi-derived sugar Trehalose restores the functional breakdown of myelin residues, stops the progression and leads to recovery from MS-like disease.” says doctoral student Rasmus Berglund. “By enhancing this process we hope one day to be able to treat and prevent age-related aspects of neuroinflammatory conditions.”

Funding: The research was carried out with grants from the Swedish Research Council, the Swedish Brain Foundation, Neuro, Region Stockholm, Astra Zeneca, Horizon 2020, the European Research Council, the Knut and Alice Wallenberg Foundation, the Margaretha af Uggla Foundation, Alltid Litt Sterkere, the Foundation of Swedish MS research, NEURO Sweden and Karolinska Institutet. There are no declared conflicts of interest.

Study Explains the Process That Exacerbates Multiple Sclerosis - Neuroscience News

Recovery from multiple sclerosis-like symptoms in mice depends upon the ability for microglia to break down the remains of damaged cells.

neurosciencenews.com

 

[mr peabody]

U of A researcher Christopher Power found that administering an anti-inflammatory drug called VX-765
through the nose slowed the progression of multiple sclerosis in a preclinical model.

Anti-inflammatory therapy shows promise in slowing progression of MS

University of Alberta | Neuroscience News | 20 Oct 2020

A new intranasal delivery system shows promise in reducing neuroinflammation and slowing the progression of Multiple Sclerosis.

Intranasal administration of an anti-inflammatory drug helped reduce disease progression in a preclinical model of Multiple Sclerosis, according to recent research out of the University of Alberta.

Christopher Power, professor in the Faculty of Medicine & Dentistry, and Leina Saito, a graduate student on his team, showed that delivering an anti-inflammatory drug to mice helped prevent damage to brain cells, effectively slowing the progression of the disease.

MS is a devastating illness with no known cause and no cure. Power’s lab seeks to better understand the disease to develop effective treatments.

“Nerves in the brain are like insulated wires, but in MS there is initially a loss of the insulation [called myelin], and then the eventual loss of the wire. Those losses are caused by inflammation. That inflammation, which we think is the driving force for MS, is our main research interest,” said Power, a neurologist in the Northern Alberta MS Clinic, co-director of the U of A’s MS Centre and member of the Neuroscience and Mental Health Institute.

His research group is particularly interested in inflammasomes, molecules that are responsible for the activation of an inflammatory response in the body. For a disease such as MS, that response must be controlled to halt the progression. Power’s lab identified a drug called VX-765 as a strong candidate therapy for MS patients.

The drug works by inhibiting caspase-1, a component of inflammasomes that promotes harmful inflammation in the body. In previous research, Power’s group saw beneficial results by delivering insulin intranasally in other models of brain inflammation, and he decided to go with that delivery route again. Using mouse models, Power dissolved VX-765 in a fluid and then injected the mixture into the nose.

“It’s a lot easier for patients because you need less of the drug. It’s a direct delivery into the brain, it doesn’t go into the circulatory system and it’s not broken down as quickly,” said Power of the intranasal delivery method.

MS is a devastating illness with no known cause and no cure.

To examine the impact of VX-765 on the nerves, Power collaborated with researcher Frank Wuest, interim chair in the U of A’s Department of Oncology and member of the Cancer Research Institute of Northern Alberta. Wuest is a world expert on positron emission tomography (PET) scanning, an imaging technique that uses radioactive substances to visualize changes in the body. Wuest used PET scans to look at brain metabolism and was able to document whether the insulation had been stripped or not after the therapeutic was delivered.

“The study shows intranasal therapy is effective in preventing demyelination and axon injury and loss, so that’s a real tonic for us to keep going,” said Power. “The loss of myelin and loss of nerves are irreversible processes, so any therapeutic that helps to slow or prevent that from happening is an exciting advance for MS research. The particular delivery method also allows the therapy to be delivered in a more precise and targeted way.”

Anti-Inflammatory Therapy Shows Promise in Slowing Progression of Multiple Sclerosis - Neuroscience News

A new intranasal delivery system shows promise in reducing neuroinflammation and slowing the progression of multiple sclerosis.

neurosciencenews.com