Cell Transplants For Neuropathy A Treatment For The Future

Today's post comes from newswise.com (see link below) and talks about another potential means of reducing neuropathic pain symptoms, this time by nerve cell transplants. As you can see, the idea is more or less still in its infancy but it's good to know that light is being seen at the ends of various long tunnels and that people are working hard to find effective treatments for neuropathy. Maybe people are waking up to the fact that this is a disease that needs urgent attention!

Chronic Pain Is Relieved by Cell Transplantation in Lab Study

Released:5/22/2012 3:25 PM EDT
Source:University of California, San Francisco (UCSF)

UCSF Scientists Aim to Use Embryonic Stem Cells for Treatment

Newswise — Chronic pain, by definition, is difficult to manage, but a new study by UCSF scientists shows how a cell therapy might one day be used not only to quell some common types of persistent and difficult-to-treat pain, but also to cure the conditions that give rise to them.

The researchers, working with mice, focused on treating chronic pain that arises from nerve injury -- so-called neuropathic pain.

In their study, published in the May 24, 2012 issue of Neuron, the scientists transplanted immature embryonic nerve cells that arise in the brain during development and used them to make up for a loss of function of specific neurons in the spinal cord that normally dampen pain signals.

A small fraction of the transplanted cells survived and matured into functioning neurons. The cells integrated into the nerve circuitry of the spinal cord, forming synapses and signaling pathways with neighboring neurons.

As a result, pain hypersensitivity associated with nerve injury was almost completely eliminated, the researchers found, without evidence of movement disturbances that are common side effects of the currently favored drug treatment.

“Now we are working toward the possibility of potential treatments that might eliminate the source of neuropathic pain, and that may be much more effective than drugs that aim only to treat symptomatically the pain that results from chronic, painful conditions,” said the senior author of the study, Allan Basbaum, PhD, chair of the Department of Anatomy at UCSF.

Although pain and hypersensitivity after injury usually resolve, in some cases they outlast the injury, creating the condition of chronic pain. Many types of chronic pain are induced by stimuli that are essentially harmless — such as light touch — but that are perceived as painful, according to Basbaum.

Chronic pain due to this type of hypersensitivity is often a debilitating medical condition. Many people suffer from chronic neuropathic pain after a bout of shingles, years or decades after the virus that causes chicken pox has been vanquished. Chronic pain is not merely prolonged acute pain, Basbaum said.

Those who suffer from chronic pain often get little relief, even from powerful narcotic painkillers, according to Basbaum. Gabapentin, an anticonvulsant first used to treat epilepsy, now is regarded as the most effective treatment for neuropathic pain. However, it is effective for only roughly 30 percent of patients, and even in those people it only provides about 30 percent relief of the pain, he said.

The explanation for neuropathic pain, research shows, is that following injury neurons may be lost, or central nervous system circuitry may change, in ways that are maladaptive, compromising signals that normally help dampen pain. These changes contribute to a state of hyper-excitability, enhancing the transmission of pain messages to the brain and causing normally innocuous stimuli to become painful.

The inhibitory neurons that are damaged in the spinal cord to cause pain hypersensitivity release a molecule that normally transmits inhibitory signals — the neurotransmitter GABA. A loss of GABA inhibition also is implicated in epilepsy and may play a role in Parkinson’s disease. Gabapentin does not mimic GABA, but it helps to compensate for the loss of inhibition that GABA normally would provide.

Basbaum’s UCSF colleagues, including study co-authors Arturo Alvarez-Buylla, PhD, and Arnold Kriegstein, MD, PhD, along with Scott Baraban, PhD, had already been experimenting with transplanting immature neurons that make GABA, using the transplanted neurons to bolster inhibitory signals in mouse models to prevent epileptic seizures and to combat a Parkinson’s-like disease.

However, in those experiments the cells — which originate in a region of the forebrain known as the medial ganglionic eminence — were transplanted within the brain itself, which is their normal home.

Upon hearing about the research, Basbaum became interested in transplanting the same cells into the spinal cord as a potential treatment for the loss of GABA-driven inhibition in neuropathic pain. Success was by no means assured, as cells normally do not survive outside their natural environments within such a complex organism.

Another co-author of the Neuron study, UCSF researcher John Rubenstein, PhD, has made major progress in identifying molecules that can be manipulated to lead an embryonic stem cell to go through developmental stages that cause it to acquire the properties of GABA neurons that derive from the medial ganglionic eminence.

According to Kriegstein, who directs the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, “This research is at a very early stage, and we’re a long way from thinking about it in human trials, but we do have a method of making cells that are like these inhibitory neurons, starting with human embryonic stem cells.”

As a step toward eventual therapies, the UCSF team plans to graft fetal human cells from the medial ganglionic eminence, or cells derived from human embryonic stem cells, into a rodent model of neuropathic pain, to see if the human cells also will alleviate neuropathic chronic pain.

“Unlike drugs, the transplanted cells can have very focused effects, depending on where they are transplanted,” Kriegstein said.

According to Alvarez-Buylla, a leading scientist among those working to define the potentialities of various cells in the developing brain at different stages, "One of the amazing properties of these cells from the medial ganglionic eminence is their unprecedented migratory capacity, which enables them to navigate through multiple terrains within the central nervous system, and to then become functionally integrated with other cells. Those properties have proved useful in other places where we have transplanted them, and now in the spinal cord.”

Joao Braz, PhD, an assistant research scientist, and Reza Sharif-Naieni, PhD, a postdoctoral fellow, both working in the Basbaum laboratory, carried out the bulk of the experiments published in Neuron. The authors have a patent pending on the treatment outlined in the study.

The study was funded by the National Institutes of Health, the Association for the Study of Pain and the Canadian Institutes of Health Research.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
http://www.newswise.com/articles/chronic-pain-is-relieved-by-cell-transplantation-in-lab-study

HEALTHY LIFE STYLE MAY BUFFER AGAINST STRESS RELATED CELL AGING

A new study from UC San Francisco is the first to show that while the impact of life's stressors accumulate overtime and accelerate cellular aging, these negative effects may be reduced by maintaining a healthy diet, exercising and sleeping well.

The study participants who exercised, slept well and ate well had less telomere shortening than the ones who didn't maintain healthy lifestyles, even when they had similar levels of stress," said lead author Eli Puterman, PhD, assistant professor in the department of psychiatry at UCSF. "It's very important that we promote healthy living, especially under circumstances of typical experiences of life stressors like death, caregiving and job loss."

The paper will be published in Molecular Psychiatry, a peer-reviewed science journal by Nature Publishing Group.

Telomeres are the protective caps at the ends of chromosomes that affect how quickly cells age. They are combinations of DNA and proteins that protect the ends of chromosomes and help them remain stable. As they become shorter, and as their structural integrity weakens, the cells age and die quicker. Telomeres also get shorter with age.

In the study, researchers examined three healthy behaviors -physical activity, dietary intake and sleep quality -- over the course of one year in 239 post-menopausal, non-smoking women. The women provided blood samples at the beginning and end of the year for telomere measurement and reported on stressful events that occurred during those 12 months. In women who engaged in lower levels of healthy behaviors, there was a significantly greater decline in telomere length in their immune cells for every major life stressor that occurred during the year. Yet women who maintained active lifestyles, healthy diets, and good quality sleep appeared protected when exposed to stress -- accumulated life stressors did not appear to lead to greater shortening.

"This is the first study that supports the idea, at least observationally, that stressful events can accelerate immune cell aging in adults, even in the short period of one year. Exciting, though, is that these results further suggest that keeping active, and eating and sleeping well during periods of high stress are particularly important to attenuate the accelerated aging of our immune cells," said Puterman.

In recent years, shorter telomeres have become associated with a broad range of aging-related diseases, including stroke, vascular dementia, cardiovascular disease, obesity, osteoporosis diabetes, and many forms of cancer.

Research on telomeres, and the enzyme that makes them, telomerase, was pioneered by three Americans, including UCSF molecular biologist and co-author Elizabeth Blackburn, PhD. Blackburn co-discovered the telomerase enzyme in 1985. The scientists received the Nobel Prize in Physiology or Medicine in 2009 for their work.

"These new results are exciting yet observational at this point. They do provide the impetus to move forward with interventions to modify lifestyle in those experiencing a lot of stress, to test whether telomere attrition can truly be slowed," said Blackburn.

Co-authors include senior author Elissa Epel, PhD, department of psychiatry, Jue Lin, PhD, department of biochemistry and biophysics, both of UCSF and Jeffrey Krauss, MD, division of physical medicine and rehabilitation at Stanford University. Lin, Epel and Blackburn are the co-founders of Telome Health Inc., a diagnostic company measuring telomere biology.

The study was supported by the Baumann Foundation and the Barney & Barbro Foundation. Puterman is supported by the National Heart, Lung and Blood Institute of the National Institutes of Health.

How Nerve Cell Stiffness Can Make You Cry From Pain

Today's post from .sciencedaily.com (see link below) may not be the easiest read but is nevertheless a fascinating one which once more looks into research progress in neuropathy treatment at a cellular and molecular level. Put in its simplest terms, it talks about the discovery that hypersensitive nerve pain may have a lot to do with nerve cell stiffness. If they can find a way to 'relax' this stiffness, they will be able to reduce pain to a manageable level. You will need to read the article to understand it better but it's worth the effort, if only to see where scientists are going in the search for ways of controlling nerve pain.

Study offers approach to treating pain 
Date: December 13, 2016 Source: European Molecular Biology Laboratory (EMBL)

For many patients with chronic pain, any light touch -- even just their clothes touching their skin -- can be agony. Scientists at EMBL and the Werner Reichardt Centre for Integrative Neuroscience (CIN) of the University of Tübingen have found a possible new avenue for producing painkillers that specifically treat this kind of pain. In a study published online today in eLife, they discovered how the stiffness of our nerve cells influences sensitivity to touch and pain.

"Being able to stop this mechanical pain could be very powerful, and it's something that current drugs are not very good at doing," says Paul Heppenstall, who led the work at EMBL.

Whether it's a light brush or a painful poke, when something touches you, receptors on the nerves under your skin sense it and carry that information to the brain. To be more precise, those receptors detect -- and respond to -- the bending of the nerve cell's membrane. The EMBL scientists have now discovered a molecule which, by influencing how stiff or bendy a nerve cell is, affects how sensitive a mouse is to touch and pain.

Heppenstall and colleagues genetically engineered mice so that they could not produce a molecule called Atat1. Working with Jing Hu's lab at CIN and Laura Andolfi at Istituto Officina dei Materiali-CNR, in Trieste, they found that the nerve cells in the affected mice became more stiff, and they became insensitive to light touch and to mechanical pain. This happened both when they prevented all of a mouse's cells from producing the molecule and when they did so just in the mouse's sensory neurons.

The Atat1 molecule is present in all cells. Scientists know that it modifies microtubules -- tiny tubes that act as transport network and scaffolding inside cells -- and that this happens in all cells, especially in nerve cells. So Heppenstall, Hu and colleagues were surprised to find that the other senses seem not to be affected in the mice.

"It could be that the molecule also affects the stiffness of nerves involved in other senses, but because stiffness is not important for detecting smells or tastes, for example, changes in cell stiffness might not have a detectable effect on those senses," says Shane Morley, who carried out the work at EMBL.

One difference that the scientists found between nerve cells that detect touch and other cells is in how their microtubules are arranged. In sensory cells, they form a ring just below the cell membrane. In other cells, they don't. The scientists think that this ring probably fine-tunes how stiff or bendy a nerve cell's membrane is, influencing how sensitive that cell -- and the animal in general -- is to touch.

The nervous system and sense of touch are similar in mice and humans, so the results likely hold true for people, too. And although problems in cell stiffness are unlikely to be at the root of most patients' hypersensitivity to touch, controlling how stiff nerve cells are could nevertheless be an effective way of treating that sensitivity.

"We're now looking for small molecules that interfere with this fine-tuning of cell stiffness, and which might one day be used to make painkillers specifically to treat this mechanical pain," says Heppenstall. "This is the first step in our sense of touch, so if we can stop the signal there, then we have a good chance of stopping everything which is downstream. And because only these touch-sensing nerve cells would be affected, there's hope that such a drug might not have many unwanted side-effects."

Story Source:

Materials provided by European Molecular Biology Laboratory (EMBL). Original written by Sonia Furtado Neves. Note: Content may be edited for style and length.


Journal Reference:
Shane J Morley, Yanmei Qi, Loredana Iovino, Laura Andolfi, Da Guo, Nereo Kalebic, Laura Castaldi, Christian Tischer, Carla Portulano, Giulia Bolasco, Kalyanee Shirlekar, Claudia M Fusco, Antonino Asaro, Federica Fermani, Mayya Sundukova, Ulf Matti, Luc Reymond, Adele De Ninno, Luca Businaro, Kai Johnsson, Marco Lazzarino, Jonas Ries, Yannick Schwab, Jing Hu, Paul A Heppenstall. Acetylated tubulin is essential for touch sensation in mice. eLife, 2016; 5 DOI: 10.7554/eLife.20813


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European Molecular Biology Laboratory (EMBL). "Study offers approach to treating pain." ScienceDaily. ScienceDaily, 13 December 2016. .


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https://www.sciencedaily.com/releases/2016/12/161213074114.htm

IMMUNE PROTEINS MOONLIGHT TO REGULATE BRAIN CELL CONNECTIONS

When it comes to the brain, "more is better" seems like an obvious assumption. But in the case of synapses, which are the connections between brain cells, too many or too few can both disrupt brain function.

Researchers from Princeton University and the University of California-San Diego (UCSD) recently found that an immune-system protein called MHCI, or major histocompatibility complex class I, moonlights in the nervous system to help regulate the number of synapses, which transmit chemical and electrical signals between neurons. The researchers report in the Journal of Neuroscience that in the brain MHCI could play an unexpected role in conditions such as Alzheimer's disease, type II diabetes and autism.

MHCI proteins are known for their role in the immune system where they present protein fragments from pathogens and cancerous cells to T cells, which are white blood cells with a central role in the body's response to infection. This presentation allows T cells to recognize and kill infected and cancerous cells.

In the brain, however, the researchers found that MHCI immune molecules are one of the only known factors that limit the density of synapses, ensuring that synapses form in the appropriate numbers necessary to support healthy brain function. MHCI limits synapse density by inhibiting insulin receptors, which regulate the body's sugar metabolism and, in the brain, promote synapse formation.

Senior author Lisa Boulanger, an assistant professor in the Department of Molecular Biology and the Princeton Neuroscience Institute (PNI), said that MHCI's role in ensuring appropriate insulin signaling and synapse density raises the possibility that changes in the protein's activity could contribute to conditions such Alzheimer's disease, type II diabetes and autism. These conditions have all been associated with a complex combination of disrupted insulin-signaling pathways, changes in synapse density, and inflammation, which activates immune-system molecules such as MHCI.

Patients with type II diabetes develop "insulin resistance" in which insulin receptors become incapable of responding to insulin, the reason for which is unknown, Boulanger said. Similarly, patients with Alzheimer's disease develop insulin resistance in the brain that is so pronounced some have dubbed the disease "type III diabetes," Boulanger said.

"Our results suggest that changes in MHCI immune proteins could contribute to disorders of insulin resistance," Boulanger said. "For example, chronic inflammation is associated with type II diabetes, but the reason for this link has remained a mystery. Our results suggest that inflammation-induced changes in MHCI could have consequences for insulin signaling in neurons and maybe elsewhere."

MHCI levels also are "dramatically altered" in the brains of people with Alzheimer's disease, Boulanger said. Normal memory depends on appropriate levels of MHCI. Boulanger was senior author on a 2013 paper in the journal Learning and Memory that found that mice bred to produce less functional MHCI proteins exhibited striking changes in the function of the hippocampus, a part of the brain where some memories are formed, and had severe memory impairments.

"MHCI levels are altered in the Alzheimer's brain, and altering MHCI levels in mice disrupts memory, reduces synapse number and causes neuronal insulin resistance, all of which are core features of Alzheimer's disease," Boulanger said.

Links between MHCI and autism also are emerging, Boulanger said. People with autism have more synapses than usual in specific brain regions. In addition, several autism-associated genes regulate synapse number, often via a signaling protein known as mTOR (mammalian target of rapamycin). In their study, Boulanger and her co-authors found that mice with reduced levels of MHCI had increased insulin-receptor signaling via the mTOR pathway, and, consequently, more synapses. When elevated mTOR signaling was reduced in MHCI-deficient mice, normal synapse density was restored.

Thus, Boulanger said, MHCI and autism-associated genes appear to converge on the mTOR-synapse regulation pathway. This is intriguing given that inflammation during pregnancy, which alters MHCI levels in the fetal brain, may slightly increase the risk of autism in genetically predisposed individuals, she said.

"Up-regulating MHCI is essential for the maternal immune response, but changing MHCI activity in the fetal brain when synaptic connections are being formed could potentially affect synapse density," Boulanger said.

Ben Barres, a professor of neurobiology, developmental biology and neurology at the Stanford University School of Medicine, said that while it is known that both insulin-receptor signaling increases synapse density, and MHCI signaling decreases it, the researchers are the first to show that MHCI actually affects insulin receptors to control synapse density.

"The idea that there could be a direct interaction between these two signaling systems comes as a great surprise," said Barres, who was not involved in the research. "This discovery not only will lead to new insight into how brain circuitry develops but to new insight into declining brain function that occurs with aging."

Particularly, the research suggests a possible functional connection between type II diabetes and Alzheimer's disease, Barres said.

"Type II diabetes has recently emerged as a risk factor for Alzheimer's disease but it has not been clear what the connection is to the synapse loss experienced with Alzheimer's disease," he said. "Given that type II diabetes is accompanied by decreased insulin responsiveness, it may be that the MHCI signaling becomes able to overcome normal insulin signaling and contribute to synapse decline in this disease."

Research during the past 15 years has shown that MHCI lives a prolific double-life in the brain, Boulanger said. The brain is "immune privileged," meaning the immune system doesn't respond as rapidly or effectively to perceived threats in the brain. Dozens of studies have shown, however, that MHCI is not only present throughout the healthy brain, but is essential for normal brain development and function, Boulanger said. A 2013 paper from her lab published in the journal Molecular and Cellular Neuroscience showed that MHCI is even present in the fetal-mouse brain, at a stage when the immune system is not yet mature.

"Many people thought that immune molecules like MHCI must be missing from the brain," Boulanger said. "It turns out that MHCI immune proteins do operate in the brain -- they just do something completely different. The dual roles of these proteins in the immune system and nervous system may allow them to mediate both harmful and beneficial interactions between the two systems."

Stem Cell Therapy For Neuropathy

Today's article from medicalexpress.com (see link below) discusses advances in the study of the potential use of stem cells to block pain signals and inflammation for neuropathy sufferers. It's not a new idea and has been seen in articles for some time now but it does seem that research progress is being made. The average neuropathy patient can be forgiven for saying; 'That's all well and good but when will our doctors be able to begin this sort of therapy with us?' It's true; the internet is littered with possibilities for the future but that's how it works and these days, we can follow developments as they happen. It's worth reminding ourselves that knowledge is a sort of power over the disease.

A step forward for stem cell therapy
July 11, 2012

Aline Betancourt, research associate professor with the Tulane Center for Stem Cell Research and Regenerative Medicine, developed a technique to produce standardized stem cells that will turn off the body’s inflammatory response. Credit: Paula Burch-Celentano (Medical Xpress) -- A new study shows the potential of a method to prepare stem cells that may provide relief from a painful diabetes complication. Aline Betancourt of the Tulane University Center for Stem Cell Research and Regenerative Medicine, with colleagues at Tulane and the Ochsner Clinic Foundation, developed a new treatment using modified stem cells to control inflammation.   

The study results released on Monday (July 9) in the journal Stem Cells Translational Medicine suggest that the use of stem cells specially prepared to turn off the body’s inflammatory response represent a promising new therapeutic strategy for diabetic peripheral neuropathy that should be further investigated. About 70 percent of diabetics have neuropathy (nerve damage) resulting from the disease, according to the National Institutes of Health. Severe peripheral neuropathy causes excruciating pain in the toes, feet, legs, hands or arms. Even a tiny amount of external pressure can be excruciating. Inflammation is considered a major culprit. Previous studies have proven mesenchymal stem cells (MSCs) are safe and effective in treating inflammatory diseases. MSCs, which are taken from adult donors, can give rise to a large number of tissue types such as bone, fat and cartilage.“The problem,” Betancourt explains, “is that the current methods for preparing these cells yield a mixed pool of undefined cells that aren’t consistently effective in the clinic. Our laboratory developed a new method that results in a consistent, uniform MSC population and optimizes their anti-inflammatory effects. We call these cells MSC2s.”When the researchers tested the MSC2 cells on mice with peripheral neuropathy, they saw a significant improvement in inflammation and other symptoms — as much as 40 percent for the MSC2 group over the mice that received no treatment. At best, there was only 14 percent improvement in those administered conventional MSCs. Provided by Tulane University

http://medicalxpress.com/news/2012-07-stem-cell-therapy.html