A NEW QUALITY CONTROL PATHWAY IN THE CELL

Proteins are important building blocks in our cells and each cell contains millions of different protein molecules. They are involved in everything from structural to regulatory aspects in the cell. Proteins are constructed as linear molecules but they only become functional once they are folded into specific three-dimensional structures. Several factors, like mutations, stress and age, can interfere with this folding process and induce protein misfolding. Accumulated misfolded proteins are toxic and to prevent this, cells have developed quality control systems just like any other production chain or manufacturing process

A team of researchers at the Centre for Genomic Regulation in Barcelona has just published a paper inScience describing a new quality control system in our cells. It is specific to the inner nuclear membrane, a specialised part of the endoplasmic reticulum (ER), a network of membranes that spreads throughout the cell and which also forms the nuclear envelope that wraps the chromosomes.

Other quality control systems have been described but exactly how misfolded proteins in the inner nuclear membrane were degraded was not known. Ombretta Foresti, Victoria Rodríguez-Vaello and Pedro Carvalho, from the Organelle Biogenesis and Homeostasis laboratory at the CRG have just described the new system. "We have found that this quality control system has two key functions. It gets rid of misfolded proteins and, surprisingly, it also helps prevent the nucleus accumulating proteins that should not be there," explains Pedro Carvalho, principal investigator of this paper.

The studies have been conducted using a unicellular model organism (Baker's yeast) but they may also apply to human physiology. The newly identified quality control system protects the nucleus by targeting foreign proteins that could enter the nucleus by mistake. This could be particularly significant in non-dividing cells where the inner nuclear membrane is isolated from the rest of the ER for long periods of time

These findings have been made possible thanks to funding from the Howard Hughes Medical Institute (HHMI) and MCCIN at the CRG in Barcelona.

New Explanation For Diabetes Related Neuropathic Pain

Today's post from Sciencedaily.com (see link below) brings a dilemma with it. A study has shown that changes in 'dendritic spines' in the brain may play an important part in explaining neuropathic pain in diabetes-related cases! Yet nowhere does it say that this is exclusively a diabetes-related occurence. The article states that the reason why diabetes can cause neuropathy is still a mystery, so there is really no reason to assume that these changes in the nerve endings in the brain only occur in diabetes patients. We need the study to include HIV-related neuropathy and many other forms too, If the dendritic spines are not altered in other forms of neuropathy, then they have some important information but at the moment, to a layman like me, it's just not clear.
 Many people with HIV looking for information on neuropathy, may skip over articles about diabetic neuropathy because they think it doesn't apply. This is generally just not true. Most of the information about diabetic neuropathy applies to all neuropathies; it's just that diabetic neuropathy is by far the most common form amongst the general population. If you ask 99 out of a 100 diabetic neuropathy patients what their symptoms are, you'll find that they are exactly the same as your own. What the researchers mean to say is that they don't really understand the processes behind why neuropathy occurs in most of its forms and tying it to one disease depends on who their target readership is. If there are any experts out there who can explain (in relatively simple terms)  the real differences in disease-based neuropathies, please let us know - very many people are interested.

Unexpected Source for Diabetic Neuropathy Pain

ScienceDaily (May 15, 2012)

Normal dendritic spines — microscopic projections on the receiving branches of nerve cells — are shown at top compared to those of diabetic rat. At bottom, spines after receiving treatment. Yale study suggests that neuropathic pain associated with diabetes may be caused by reshaping of these spines in nerve cells, and might be treated by drugs. (Credit: Image courtesy of Yale University)

Nearly half of all diabetics suffer from neuropathic pain, an intractable, agonizing and still mysterious companion of the disease. Now Yale researchers have identified an unexpected source of the pain and a potential target to alleviate it.

A team of researchers from Yale and the West Haven Veterans Affairs Medical Center describes in the May 15 issue of the Journal of Neuroscience how changes in the structure of dendritic spines -- microscopic projections on the receiving branches of nerve cells -- are associated with pain in laboratory rats with diabetes.

"How diabetes leads to neuropathic pain is still a mystery," said Andrew Tan, an associate research scientist in neurology at the Yale School of Medicine and lead author of the study. "An interesting line of study is based on the idea that neuropathic pain is due to faulty 'rewiring' of pain circuitry."
With a growing number of diabetics, the condition represents a huge unmet medical need. Once neuropathic pain is established, it is a lifelong condition.

"Here we reveal that these dendritic spines, first studied in memory circuit processing, also contribute to the sensation of pain in diabetes," Tan said. A single neuron may contain hundreds to thousands of dendritic spines.

The Yale team led by Tan and senior author Dr. Stephen G. Waxman, the Bridget Marie Flaherty Professor of Neurology, professor of neurobiology and pharmacology,found abnormal dendritic spines were associated with the onset and maintenance of pain. They also found that a drug that interferes with formation of these spines reduced pain in lab animals, suggesting that targeting abnormal spines could be a therapeutic strategy.

Tan said that these dendritic spines in nerve cells seem to store memory of pain, just as they are crucial in memory and learning in the human brain.

"We have identified a single, key molecule that controls structural changes in these spines and hopefully we can develop therapeutic approaches that target that molecule and reduce diabetic pain," Waxman said.

Other authors on the paper are Omar A. Samad, Tanya Z. Fischer, Peng Zhao and Anna-Karin Persson,
The research was funded by the Department of Veterans Affairs.

http://www.sciencedaily.com/releases/2012/05/120515203056.htm

SCIENTISTS DISCOVER A NEW SLEEP NODE IN THE BRAIN

A sleep-promoting circuit located deep in the primitive brainstem has revealed how we fall into deep sleep. Discovered by researchers at Harvard School of Medicine and the University at Buffalo School of Medicine and Biomedical Sciences, this is only the second "sleep node" identified in the mammalian brain whose activity appears to be both necessary and sufficient to produce deep sleep.

Published online in August in Nature Neuroscience, the study demonstrates that fully half of all of the brain's sleep-promoting activity originates from the parafacial zone (PZ) in the brainstem. The brainstem is a primordial part of the brain that regulates basic functions necessary for survival, such as breathing, blood pressure, heart rate and body temperature.

"The close association of a sleep center with other regions that are critical for life highlights the evolutionary importance of sleep in the brain," says Caroline E. Bass, assistant professor of Pharmacology and Toxicology in the UB School of Medicine and Biomedical Sciences and a co-author on the paper.

The researchers found that a specific type of neuron in the PZ that makes the neurotransmitter gamma-aminobutyric acid (GABA) is responsible for deep sleep. They used a set of innovative tools to precisely control these neurons remotely, in essence giving them the ability to turn the neurons on and off at will.

"These new molecular approaches allow unprecedented control over brain function at the cellular level," says Christelle Ancelet, postdoctoral fellow at Harvard School of Medicine. "Before these tools were developed, we often used 'electrical stimulation' to activate a region, but the problem is that doing so stimulates everything the electrode touches and even surrounding areas it didn't. It was a sledgehammer approach, when what we needed was a scalpel."

"To get the precision required for these experiments, we introduced a virus into the PZ that expressed a 'designer' receptor on GABA neurons only but didn't otherwise alter brain function," explains Patrick Fuller, assistant professor at Harvard and senior author on the paper. "When we turned on the GABA neurons in the PZ, the animals quickly fell into a deep sleep without the use of sedatives or sleep aids."

How these neurons interact in the brain with other sleep and wake-promoting brain regions still need to be studied, the researchers say, but eventually these findings may translate into new medications for treating sleep disorders, including insomnia, and the development of better and safer anesthetics.

"We are at a truly transformative point in neuroscience," says Bass, "where the use of designer genes gives us unprecedented ability to control the brain. We can now answer fundamental questions of brain function, which have traditionally been beyond our reach, including the 'why' of sleep, one of the more enduring mysteries in the neurosciences."

The work was funded by the National Institutes of Health.

PLUCK HAIR IN A SPECIFIC PATTERN TO GROW NEW HAIR

 

If  there's a cure for male pattern baldness, it might hurt a little. A team led by USC Stem Cell Principal Investigator Cheng-Ming Chuong has demonstrated that by plucking 200 hairs in a specific pattern and density, they can induce up to 1,200 replacement hairs to grow in a mouse. These results are published in the April 9 edition of the journal Cell.

It is a good example of how basic research can lead to a work with potential translational value," said Chuong, who is a professor of pathology at the Keck School of Medicine of USC. "The work leads to potential new targets for treating alopecia, a form of hair loss."

The study began a couple of years ago when first author and visiting scholar Chih-Chiang Chen arrived at USC from National Yang-Ming University and Veterans General Hospital, Taiwan. As a dermatologist, Chen knew that hair follicle injury affects its adjacent environment, and the Chuong lab had already established that this environment in turn can influence hair regeneration. Based on this combined knowledge, they reasoned that they might be able to use the environment to activate more follicles.

To test this concept, Chen devised an elegant strategy to pluck 200 hair follicles, one by one, in different configurations on the back of a mouse. When plucking the hairs in a low-density pattern from an area exceeding six millimeters in diameter, no hairs regenerated. However, higher-density plucking from circular areas with diameters between three and five millimeters triggered the regeneration of between 450 and 1,300 hairs, including ones outside of the plucked region.

Working with Arthur D. Lander from the University of California, Irvine, the team showed that this regenerative process relies on the principle of "quorum sensing," which defines how a system responds to stimuli that affect some, but not all members. In this case, quorum sensing underlies how the hair follicle system responds to the plucking of some, but not all hairs.

Through molecular analyses, the team showed that these plucked follicles signal distress by releasing inflammatory proteins, which recruit immune cells to rush to the site of the injury. These immune cells then secrete signaling molecules such as tumor necrosis factor alpha (TNF-α), which, at a certain concentration, communicate to both plucked and unplucked follicles that it's time to grow hair.

"The implication of the work is that parallel processes may also exist in the physiological or pathogenic processes of other organs, although they are not as easily observed as hair regeneration," said Chuong.

NOW NEW DEVICE THAT CAN SLOW REVERSE HEART FAILURE

Scientists have developed a new implantable device that can help in controlling and reversing heart failure, it has been reported.

According to lead researcher Dr. William Abraham of The Ohio State University Wexner Medical Center the new device has shown promising results in the first trial to determine safety and effectiveness in patients.

Researchers at seven U.S. centers examined an extra-aortic counterpulsation system called C-Pulse, made by Sunshine Heart Inc. It's a cuff that wraps around the aorta and syncs with the patient's heartbeat, rapidly inflating and deflating a small balloon to help squeeze blood through the aorta to circulate throughout the body.

It's powered through a wire that exits the abdomen and connects to an external driver worn by the patient. The driver could be plugged in or battery-powered.

The most common adverse effect during the trial was infection of the exit site, experienced by 8 out of 20 participants. Researchers noted that stricter guidelines for exit site management, wound care and antibiotic therapy could reduce that risk in future studies.

There were no hospitalizations among the participants for stroke, thrombosis, sepsis or bleeding, which often occurs in patients using left ventricular assist devices (LVADs). The researchers said this was due to the device remaining outside the bloodstream.

Another important difference was the C-Pulse device could be temporarily turned off and disconnected, allowing patients some conveniences that an LVAD doesn't permit.

The study is published in the Journal of American College of Cardiology Heart Failure. 

BL 7050 New Drug For Neuropathic Pain

Following on from yesterday's post, today's article from sciencedaily.com (see link below) goes into more detail about the potassium-based neuropathy drug (at the moment, charmingly named, BL-7050) developed in Israel. It is still in the trials and testing stage, so won't be appearing on your pharmacist's shelves for some time yet but it sounds promising. The reason for posting two similar stories after each other, is to give a little more weight to the subject. The more serious websites devote attention to new drugs, the more they are likely to be real prospects of progress.

A New Drug to Manage Resistant Chronic Pain

ScienceDaily (Apr. 30, 2012)

Neuropathic pain, caused by nerve or tissue damage, is the culprit behind many cases of chronic pain. It can be the result of an accident or caused by a variety of medical conditions and diseases such as tumors, lupus, and diabetes. Typically resistant to common types of pain management including ibuprofen and even morphine, neuropathic pain can lead to lifelong disability for many sufferers.

Now a drug developed by Tel Aviv University researchers, known as BL-7050, is offering new hope to patients with neuropathic pain. Developed by Prof. Bernard Attali and Dr. Asher Peretz of TAU's Department of Physiology and Pharmacology at the Sackler Faculty of Medicine, the medication inhibits the transmission of pain signals throughout the body. In both in-vitro and in-vivo experiments measuring electrical activity of neurons, the compound has been shown to prevent the hyper-excitability of neurons -- protecting not only against neuropathic pain, but epileptic seizures as well.

The medication has been licensed by Ramot, TAU's technology transfer company, for development and commercialization by BioLineRx, an Israeli biopharmaceutical development company.

Targeting potassium for pain control

According to Prof. Attali, the medication works by targeting a group of proteins which act as a channel for potassium. Potassium has a crucial role in the excitability of cells, specifically those in the nervous system and the heart. When potassium channels don't function properly, cells are prone to hyper-excitability, leading to neurological and cardiovascular disorders such as epilepsy and arrhythmias. These are also the channels that convey pain signals caused by nerve or tissue damage, known as neuropathic pain.

With few treatment options available for neuropathic pain, Prof. Attali set out to develop a medication that could bind to and stabilize the body's potassium channels, controlling their hyper-excitability and preventing the occurrence of pain by keeping the channels open for the outflow of potassium. This novel targeting approach has been recently reported in the journal PNAS.

Inducing calm in the neurons

Understanding the mechanism that controls these channels has been crucial to the development of the drug. By successfully controlling the excitability of the neurons, Prof. Attali believes that BL-7050 could bring relief to hundreds of millions of patients around the world who suffer from neuropathic pain. The medication will reach the first phase of clinical trials in the near future.

In pre-clinical trials, BL-7050 was tested in rats experiencing both epilepsy and neuropathic pain and was found to be efficient in protecting against both when taken as a pill. While on the medication, rats were no longer affected by stimuli that had previously caused pain. Measures in the electrical activities of neurons also revealed that the medication was able to induce "calm" in the neurons, inhibiting pain pathways.

The above story is reprinted from materials provided by American Friends of Tel Aviv University.
http://www.sciencedaily.com/releases/2012/04/120430124715.htm

HIGHLY EFFECTIVE NEW ANTI CANCER DRUG SHOWS FEW SIDE EFFECTS IN MICE

A new drug, known as OTS964, can eradicate aggressive human lung cancers transplanted into mice, according to a report in Science Translational Medicine. The drug, given as a pill or by injection, inhibits the action of a protein that is overproduced by several tumor types, including lung and breast, but is rarely expressed in healthy adult tissues. Without this protein, cancer cells fail to complete the cell-division process and die.

When taken by mouth, the drug was well tolerated with limited toxicity. An intravenous form, delivered within a liposome, was just as effective with fewer side effects. Both approaches -- described in the October 22, 2014 issue of Science Translational Medicine -- led to complete regression of transplanted tumors.

"We identified the molecular target for this drug ten years ago, but it took us nearly a decade to find an effective way to inhibit it," said study author Yusuke Nakamura, MD, PhD, professor of medicine at the University of Chicago and deputy director of the University's Center for Personalized Therapeutics. "We initially screened 300,000 compounds and then synthesized more than 1,000 of them, and found a few that were likely to work in humans. We focused on the most effective. We think we now have something very promising."

OTS964 targets TOPK (T -- lymphokine-activated killer cell -- originated protein kinase), a protein that is produced by a wide range of human cancers and is believed to promote tumor growth. High TOPK expression correlates with poor prognosis in patients with breast and lung cancer.

Initial studies of the drug, and a precursor called OTS514, found they were effective in killing cancer cells. But they could disrupt the production of new red and white blood cells, causing hematopoietic toxicity such as mild anemia and increasing the risk of infection. At the same time, the drugs increased the production of platelets, which help in blood clotting.

When the researchers encapsulated the drugs in liposomes -- microscopic bubbles similar to a cell membrane, commonly used to transport drugs within the body -- the drug no longer caused this decrease in red and white blood cells. This approach "completely eliminated the hematopoietic toxicity," the researchers wrote.

They tested OTS964 alone and in liposomes in mice with a highly aggressive human lung tumor known as LU-99. They allowed the tumors to grow to 150 cubic millimeters -- about the size of a raisin -- and then administered the drug intravenously to six mice, twice a week for three weeks. The tumors shrank rapidly and continued to shrink even after treatment stopped. In five of the six mice, the tumors completely disappeared -- three within 25 days of the first treatment and two within 29 days. Mice that received the liposome-coated drug had no detectable toxicity.

The drug also proved effective when taken in larger doses by mouth. Six mice with LU-99 lung tumors were fed 100 milligrams per kilogram of OTS964 every day for two weeks. Again, continuous tumor shrinkage was observed after the final dose of the drug. In all six mice the tumors completely regressed. All of the mice had low white-blood-cell counts after treatment, but they recovered within two weeks.

Although this was a small study, the outcome was dramatic. Seeing these results was a "quite exciting moment," said Nakamura, who stepped down from his role as Director in the Japanese Government's Office of Medical Innovation to join the faculty at the University of Chicago in April 2012. "It is rare to see complete regression of tumors in a mouse model," he said. "Many drugs can repress the growth, but it is uncommon to see them eradicated. This has rarely been reported."

Similar studies of the drug's effects on tumor cells growing outside the body enabled the researchers to videotape the process as the cancer cells died. TOPK appears to play a central role late in cytokinesis, the final stage in cell division. Dividing cancer cells would begin to separate into two new cells, but were unable to fully disconnect, retaining an intercellular bridge.

"Without TOPK the cells can't seem to divide; they can't make the break," Nakamura said. "They can't complete the process. Instead they remain tethered by a tiny bridge. When that finally breaks apart, they can't close the membrane. Everything within the cells spills out, they suffer and then die."

TOPK may provide a good drug target for several types of cancer. This study involved primarily lung cancers, but the gene is frequently upregulated in breast, brain, liver, bladder and other solid tumors as well as certain types of leukemia. The researchers are working with oncologists at the University to begin a phase-1 clinical trial as soon as the fall of 2015.

NEW CHOLESTEROL GUIDELINES REDUCE HEART ATTACKS

Study from UT Southwestern researchers found that recently introduced cholesterol guidelines would significantly reduce new cardiovascular events, when compared to treatment based on previous cholesterol guidelines.

The research identified Dallas Heart Study participants in the 30 to 65 age range who would have newly qualified for statin use under the new cholesterol guidelines introduced in 2013 by the American College of Cardiology (ACC) and the American Heart Association (AHA).

In this subset of patients, the study predicted that 3.6 to 4.9 cardiovascular events would have been prevented for every 1,000 people screened and treated according to the new guidelines rather than the old guidelines (using a risk-reduction factor of 30 percent to 45 percent, depending on the statin dosage). The Dallas Heart Study is a multiethnic, population-based study of thousands of Dallas County adults whose cardiovascular health has been followed for 10 years.

Projecting these findings onto the larger Dallas County population, about 4,500 serious heart problems would have been prevented in individuals 30 to 65 years of age over a 10-year period by following the new cholesterol guidelines.

When the new guidelines were introduced -- replacing previous guidelines from the National Cholesterol Education Program/Third Adult Treatment Panel -- they provoked heated debate over the sizeable increase in statin eligibility. However, the UT Southwestern study supports the merit of the new cholesterol guidelines, as well as increased statin use.

"This is one of the first studies to carefully predict the implications of the new guidelines in the general population beyond just the amount of increase in statin use," said Dr. Amit Khera, Associate Professor of Internal Medicine and Director of the Preventive Cardiology Program at UT Southwestern. "Does it look like these new guidelines will prevent heart attacks and strokes? The answer is, 'yes,'" he said.

Dr. Khera is senior author of the recently published study, which appeared inCirculation: Cardiovascular Quality and Outcomes.

The 2013 ACC/AHA Cholesterol Guidelines recommend statins for patients with existing atherosclerotic cardiovascular disease, type 2 diabetes, and very high levels of LDL cholesterol, as well as for patients with a high 10-year risk for heart disease.

The previous guidelines from the National Cholesterol Education Program/Third Adult Treatment Panel were based on a different formula that involved targeting specific cholesterol levels. Some patients fall out of statin eligibility under the new guidelines, but some 12.8 million more are newly eligible.

Among Dallas Heart Study participants who actually experienced a cardiovascular event, 37.1 percent more of those patients would have been placed on statins if the new guidelines had been in place. Among participants who did not experience a cardiovascular event, only 3.9 percent more patients would have been prescribed statins.

"There has been a lot of emphasis on the increased use of statins and a lot of emphasis on the risk calculator," said Dr. Khera, who holds the Dallas Heart Ball Chair in Hypertension and Heart Disease. "Yes, there is some additional statin use, but according to our results, this use seems appropriate, at least in this age group."

Whats New On The Neuropathy Research Front Webinar Vid

Today's YouTube video is full of lots of useful information from a recent Neuropathy Association webinar. Unfortunately, the sound is somewhat disembodied and often sounds like those irritating, computer-generated voices but the content is valuable and worth looking at and listening to if you have a free half hour. Be warned, it can be somewhat technical but the slides do help explain the text.

"What New Neuropathy Research Can We Be Hopeful For?" - 2014 Webinar
Published on 17 Jul 2014




https://www.youtube.com/watch?v=wBbK5oKWHzA#t=169

Zebra Fish The New Rats In Nerve Damage Research

Today's fascinating post from medicaldaily.com (see link below) looks at how zebra fish are being used to study how nerve damage progresses with certain neurological diseases (eg neuropathy). The fact that these fish have an 82% likeness with humans in terms of proteins means that results of studies are less likely to be misleading than those involving other research animals. We've heard of various sea creatures being used to study human neurology and developing nerve damage treatments before but apparently studying myelin sheath degradation in Zebra fish brings up many close comparisons with the same cause of nerve damage in humans but how did they ever discover that in the first place!!

Zebrafish, 82% Similar To Humans, Reveal New Insights On Neurological Disorders And Treatments
By Anoopa Singh | Jun 26, 2013

Zebrafish reveal much about neurological disorders and how to treat them.

Neurological disorders in humans are often difficult to study in human brains. As a result, animal models need to be used to simulate the workings of the human nervous system. Usually, scientists will rely on mice, but recently, the use of zebrafish has become popular due to the animal's utility.

Charcot—Marie—Tooth disease (CMT) is causes by a hereditary genetic disorder that affects the nerves that branch throughout the body in young adults. The disease leads to nerve damage and causes a weakness of muscles, foot and hand deformity, loss of muscle mass, and numbness in the lower body. CMT eventually leads to disability and a loss in sensation in the places most affected.

A new study using zebrafish, done by Andrew Grierson, Ph.D., of University of Sheffield, has revealed a great deal about CMT and potential therapies. Humans and zebrafish have proteins that are 82 percent alike — this is important because it indicates that zebrafish are suitable in studies that compare results to potential treatments for diseases in humans. When researchers altered the genes of zebrafish to be the same as patients of CMT, similar symptoms were seen as the fish aged. Once they matured into adulthood, the fish lost the ability to swim properly. The scientists feel that the difficulties in swimming can be paralleled to the difficulties humans face in walking after CMT has fully developed.

Using the zebrafish, researchers were able to identify what goes wrong in neurons as a result of CMT for the first time. They saw that the myelin sheaths around neurons began to degrade. Similarly, the far branches of nerve cells also started to degrade, leading to the sensations of pain, as messages like sensation could not travel up and down this part of the neuron anymore. Both of these issues led to the pain and neurodegeneration suffered by CMT patients.

The researchers have said that all of this would not have been clear in any other animal. In other animals, the disease starts its effects very early in development, but in humans, disease onset is usually in adolescence. This difference in other animals skews results and makes findings inconsistent with the disease's effects in humans. Grierson said, "Using zebrafish we were able to develop a model with an adult onset, progressive phenotype with predominant symptoms of motor dysfunction similar to [what happens in humans]."

He added that while we know much about other neurodegenerative diseases, others seem to escape our grasp. "Motor neurons are the largest cells in our bodies, and as such they are highly dependent on a cellular transport system to deliver molecules through the long nerve cell processes which connect the spinal cord to our muscles," he continued. "We already know that defects in the cellular transport system occur early in the development of diseases such as Alzheimer's disease, Motor Neuron Disease and spastic paraplegia. Using our zebrafish model we have found that similar defects in transport are also a key part of the disease process in CMT

Now that so much has been found out about the way CMT changes neurons for the worst, researchers can start to develop targeted therapies and treatments for the disease. There is currently no cure for CMT, nor are there any drugs that can help manage its symptoms. Patients often depend on physical or occupational therapies or surgeries for relief from symptoms.
 
While a cure may not be made tomorrow, the prospect of it and improved disease management therapies now exist.

Source: Chapman AL, Bennett EJ, Ramesh T, De Vos KJ, Grierson AJ. Axonal Transport Defects in a Mitofusin 2 Loss of Function Model of Charcot-Marie-Tooth Disease in Zebrafish. PLOS ONE. 2013.

http://www.medicaldaily.com/zebrafish-82-similar-humans-reveal-new-insights-neurological-disorders-and-treatments-247168#92xi6cLxdeJUUlFI.99

NKTR 171 A New Sodium Channel Blocker For Nerve Pain

 Normally I wouldn't consider publishing a pharmaceutical company's own promotion material - this site has a policy of not advertising for third parties. However, today's post from pipelinereview.com (see link below) can be seen as a rare exception because of its newsworthiness for neuropathy patients. It talks about another drug treatment that, at the moment only has a series of letters and numbers as its name. Eventually, it will end up with a more customer-friendly name but until then it is known as NKTR-171.
It's a new sodium channel blocker which experienced neuropathy patients will recognise as something which dampens down neural excitability in the sodium channels of the nervous system. Unlike the anti-epileptics and other drugs that are widely used for this purpose, this one is designed to work on the peripheral nerves (which most of us have trouble with) and avoid the side-effects in the central nervous system which make, anticonvulsants, opioids and antidepressants so unpleasant for many. In that respect, it will make a welcome alternative to some current treatments. It certainly reflects the current energy being put into studying pain in the nervous system and the means to reduce it. Hopefully within a few years, effective treatments with less side effects will emerge.
 

 Nektar Presents Positive Preclinical Data for NKTR-171, A Novel Sodium Channel Blocker to Treat Neuropathic Pain, at 41st Annual Meeting of the Society for Neuroscience 
15 Oct 2012

NKTR-171 Demonstrates Dose-Dependent Analgesia with Significantly Reduced CNS-Related Side Effects in Preclinical Studies

SAN FRANCISCO, CA, USA I October 15, 2012 I Nektar Therapeutics (NKTR) today announced that preclinical data for NKTR-171, a new investigational drug candidate to treat neuropathic pain, was presented at the 41st Annual Meeting of the Society for Neuroscience: Neuroscience 2012. NKTR-171 is a novel sodium channel blocker designed to act in the periphery in order to treat neuropathic pain while avoiding the serious central nervous system (CNS) side effects associated with current therapies, including anti-epileptic and anti-convulsant medications, such as gabapentinoids.

Neuropathic pain, also known as nerve pain, is a type of chronic pain that occurs when nerves become injured or damaged by systemic disease, infections, autoimmune disease, or physical trauma due to toxins or injuries. It is estimated to effect more than 20 million people in the U.S. alone.1

"Sodium channels have long been known to play a significant role in the changes in neuronal excitability that lead to neuropathic pain," said Stephen Doberstein, Ph.D., Senior Vice President and Chief Scientific Officer of Nektar Therapeutics. "We are extremely pleased that NKTR-171 exhibits effective analgesia in multiple neuropathic pain models without generating the CNS side effects observed with current therapies used to treat neuropathic pain. We look forward to continuing to prepare NKTR-171 for our first human studies, which are planned for 2013."

In a series of in vitro and in vivo preclinical studies examining the pharmacokinetics and efficacy of NKTR-171, NKTR-171 effectively blocks the inactivated state of sodium channel cells and, at the same time, demonstrates a significantly reduced brain to plasma ratio when compared to currently-approved sodium channel blockers. In well-validated animal models of persistent neuropathic pain, NKTR-171 shows superior or comparable efficacy to gabapentin. In addition, at analgesic doses, NKTR-171 did not significantly impair motor coordination in an established preclinical model of sedative potential in animals, suggesting that the therapeutic index (the ability to provide analgesia at doses that do not cause significant side effects) could potentially be greater for NKTR-171 than for currently available therapies.

These data presented in Abstract #81.06/JJ11 at the Society for Neuroscience Annual Meeting can be found on Nektar's website at:

http://www.nektar.com/pdf/pipeline/SFN_2012_NKTR_171_poster.pdf

About NKTR-171

NKTR-171 is a new sodium channel blocker that was designed to block sodium channels in the peripheral nervous system and was created using Nektar's advanced polymer conjugation technology. By selectively restricting the molecule to the periphery, NKTR-171 is intended to provide analgesia for neuropathic pain conditions without the severe sedation and other CNS side effects associated with current therapies used in the treatment of neuropathic pain. In preclinical testing, NKTR-171 demonstrates dose-dependent and effective pain relief without exhibiting sedative effects at analgesic doses.

About Neuropathic Pain

Neuropathic pain, also known as nerve pain or peripheral neuropathy, is the result of nerve damage and can be caused by such diverse conditions as diabetes, shingles, cancer, HIV, multiple sclerosis and fibromyalgia, as well as injury or trauma to the nerves. According to the Neuropathy Association, an estimated 1 in 15 Americans suffer from peripheral neuropathy1. Its prevalence is particularly high among diabetes patients and incidence increases with age1. Though neuropathic pain is a very common condition, the symptoms of it can be highly variable, including numbness, tingling, and pricking sensations, sensitivity to touch, or burning sensations, making diagnosis difficult. If left untreated, peripheral neuropathy can lead to permanent nerve damage2.

Today, medicines that act by blocking sodium or calcium channels such as the gabapentinoids and anti-epileptic medications, are used in the treatment of neuropathic pain but are known to cause serious CNS-related side effects, such as sedation and dizziness. Sodium channel blockers, such as Lidocaine, are known to be effective in addressing peripheral nerve pain, however the lack of an oral form limits its utility2. In spite of the shortcomings of medications currently prescribed for neuropathic pain, total U.S. sales in 2011 were $2.5 billion3.

About Nektar

Nektar Therapeutics is a biopharmaceutical company developing novel therapeutics based on its PEGylation and advanced polymer conjugation technology platforms. Nektar has a robust R&D pipeline of potentially high-value therapeutics in oncology, pain and other therapeutic areas. In the area of pain, Nektar has an exclusive worldwide license agreement with AstraZeneca for naloxegol (NKTR-118), an investigational drug candidate, which is being evaluated in Phase 3 clinical studies as a once-daily, oral tablet for the treatment of opioid-induced constipation. This agreement also includes NKTR-119, an earlier stage development program that is a co-formulation of naloxegol and an opioid. NKTR-181, a novel mu-opioid analgesic candidate for chronic pain conditions, is in Phase 2 development in osteoarthritis patients with chronic knee pain. NKTR-192, a novel mu-opioid analgesic in development to treat acute pain is in Phase 1 clinical development. In oncology, etirinotecan pegol (NKTR-102) is being evaluated in a Phase 3 clinical study (the BEACON study) for the treatment of metastatic breast cancer and is also in Phase 2 studies for the treatment of ovarian and colorectal cancers.

Nektar's technology has enabled eight approved products in the U.S. or Europe through partnerships with leading biopharmaceutical companies, including Affymax's OMONTYS® for anemia, UCB's Cimzia® for Crohn's disease and rheumatoid arthritis, Roche's PEGASYS® for hepatitis C and Amgen's Neulasta® for neutropenia. Additional development-stage products that leverage Nektar's proprietary technology platform include Baxter's BAX 855, a long-acting PEGylated rFVIII program, which is in Phase 1 clinical development.

Nektar is headquartered in San Francisco, California, with additional operations in Huntsville, Alabama and Hyderabad, India. Further information about the company and its drug development programs and capabilities may be found online at http://www.nektar.com.

SOURCE: Nektar Therapeutics

http://www.pipelinereview.com/index.php/2012101549185/Small-Molecules/Nektar-Presents-Positive-Preclinical-Data-for-NKTR-171-A-Novel-Sodium-Channel-Blocker-to-Treat-Neuropathic-Pain-at-41st-Annual-Meeting-of-the-Society-for-Neuroscience.html

New Topical Salve For Neuropathic Pain

Today's post from painresearchforum.org (see link below) takes a look at another interesting development involving using a topical salve to restore nerve function. The ever-suffering lab-mice have been the recipients of the trials thus far and it seems years away from  something that might be given to human patients on prescription but it's an interesting story. Basically it involves applying a non-peptide GDNF receptor agonist (XIB4035) to for instance, the feet. How it works is tricky to understand and may even seem illogical to most people but every new finding is worth reading about and keeping in mind for the future. The best treatments have often emerged from such seemingly improbable sources.

Topical Compound Boosts Trophic Factor Actions to Stem Neuropathy
Drug restores thermal nociception in two mouse models of small fiber neuropathy
By Stephani Sutherland on 19 Feb 2014

The term small fiber neuropathy (SFN) encompasses a mixed bag of conditions with a unifying element: damage or malfunction in unmyelinated peripheral nerves. In new work from Gabriel Corfas and colleagues at Harvard Medical School, Boston, US, a salve containing a compound that increases glial-derived neurotrophic factor (GDNF) activity restored lost pain sensation in two mouse models of SFN and prevented loss of nerve endings in one of them.

The work was published January 21 in the Proceedings of the National Academy of Sciences (PNAS).

The symptoms of SFN seem paradoxical: Many people experience both pain and numbness. Nerve damage can arise from diabetes, injury, autoimmune attack, or cancer (or its treatment), but many cases of SFN have mysterious origins.

“There is a desperate need in the field to develop pathogenesis-based specific treatments to treat painful symptoms in patients with peripheral neuropathies,” wrote Ahmet Höke of Johns Hopkins School of Medicine, Baltimore, US, in a commentary on the work published January 28 in PNAS (Höke, 2014).

While the current work did not look at painful symptoms of neuropathy—the experimenters measured loss of sensation to painful heat—it does hold out the possibility that a topical, small molecule treatment might be capable of rescuing lost innervation to the skin.

Derek Molliver, a neuroscientist at the University of Pittsburgh, US, says the potential is tremendous. “If you could apply something topically to restore nerve function, that would be phenomenal. Obviously, this would be worlds better than intrathecal injections.”

Co-first authors Kristian Hedstrom and Joshua Murtie used a mouse model of SFN the group had previously developed called line-D (Chen et al., 2003). The transgenic mice express non-functional receptors for the epidermal growth factor receptor ErbB specifically on non-myelinating Schwann cells, a type of glial cell that supports the peripheral axons of C-fiber neurons. When their support cells fail, C-fiber endings retract, and the sensory neurons eventually die. By a few weeks of age, the mice display deficits in the ability to sense painful heat.

In line-D mice, peripheral nerves are deficient in GDNF, and the new study shows that genetically augmenting GDNF production in the skin reversed the deficits in thermal nociception. Molliver pointed out that, like other models of peripheral neuropathy in which nerves lose contact with their target tissue, the line-D mouse actually models loss of trophic support, so the improvement with replacement of GDNF is perhaps not surprising.

Moving to a more pharmacological approach, the researchers asked whether topical application of a non-peptide GDNF receptor agonist (XIB4035) might have the same effect. They applied a cream containing XIB4035 to the hind paws of the mice beginning at three weeks of age and tested thermal nociception every seven days. While vehicle-treated line-D mice showed progressive loss of thermal nociception, line-D mice treated with XIB4035 showed no sensory loss. Line-D mice left untreated until four weeks already showed severe neuropathy symptoms that improved with XIB4035, but symptoms returned if treatment was halted, suggesting an ongoing need for the drug. Wild-type mice displayed normal sensation regardless of treatment.

The treatment also prevented the decrease in epidermal C-fiber density seen in the mutant mice, suggesting that treatment stabilized sensory nerves and prevented retraction. “Because XIB4035 was able to restore epidermal nerve fiber density in line-D, I am hopeful that it can have a positive effect as a regenerative therapy in peripheral neuropathies in people,” Höke told PRF in an email.




Image: Treatment with XIB4035 starting at postnatal day 28 increases labeling for isolectin-B4 (IB4), a marker for nonpeptidergic fibers, in the dorsal spinal cord. Left: Vehicle-treated wild-type mice display normal appearance of IB4+ (green) and TRPV1+ (red) nerve terminals. Center: Vehicle-treated line-D mice display complete absence of IB4 labeling. Right: XIB4035-treated line-D mice show presence of IB4+ fibers. No differences were observed in TRPV1 labeling between wild-type and line-D mice. Credit: From Hedstrom, Murtie, et al., 2014, © the authors.

To test a more clinically relevant mouse model of SFN, the team looked at streptozotocin-induced diabetic neuropathy. The diabetic mice showed a loss of thermal nociceptive sensation by the age of eight weeks. Mice treated with topical XIB4035 cream starting at the onset of diabetes displayed thermal sensitivity midway between that of healthy and untreated diabetic mice, which lasted throughout treatment. Interestingly, unlike in the line-D mice, XIB4035 treatment did not rescue intraepidermal nerve fiber density in the diabetic mice, suggesting that treatment improved sensation differently in the two models. “We were surprised by that finding,” said Corfas. More work needs to be done in order to understand how sensation was restored without regrowth of the missing fibers, he added.

Almost as an afterthought, Corfas told PRF, the team tested XIB4035 in a human neuroblastoma cell line to confirm the compound’s effects on human GDNF receptors. XIB4035 had previously been described as a competitive agonist at GDNF receptor α1 (GFRα1; Tokugawa et al., 2003), but unexpectedly—and unlike GFRα agonists—XIB4035 by itself had no effect on the receptor. Rather, the drug potentiated the effects of GDNF or artemin, another GFRα agonist. Further experiments confirmed that the drug bolstered activation of three different GFRα receptors by respective agonists, but had no effect on signaling by a different trophic factor, nerve growth factor (NGF), and its receptor TrkA, which are found on a different population of sensory neurons than GDNF-family receptors.

That last experiment could turn out to be the big boon that would give XIB4035 an advantage over an agonist as a therapeutic drug. “This finding led us to understand that this was a positive modulator,” Corfas told PRF. “As a modulator, its activity is restricted to the place where you have both ligands and receptors,” he said. “The drug gives a subtle but effective boost in signaling by endogenous molecules, rather than saturating the system in artificial ways.”

Previous reports had shown that GDNF and related trophic factors injected into the paw led to thermal hypersensitivity in healthy mice (Malin et al., 2006; Elitt et al., 2006). Importantly, the GDNF-augmenting treatment did not change mechanical or thermal sensitivity in healthy mice.

The effects the drug would have in animal models or patients with painful neuropathy remain to be seen. In any case, as Höke wrote, the enhancement of trophic factor signaling with this small molecule offers the hope of targeting the pathology of SFN itself.

Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California, US.

http://www.painresearchforum.org/news/37375-topical-compound-boosts-trophic-factor-actions-stem-neuropathy

RAPID AND DURABLE PROTECTION AGAINST EBOLA VIRUS WITH A NEW VACCINE

One shot of an experimental vaccine made from two Ebola virus gene segments incorporated into a chimpanzee cold virus vector (called chimp adenovirus type 3 or ChAd3) protected all four macaque monkeys exposed to high levels of Ebola virus 5 weeks after inoculation, report National Institutes of Health (NIH) scientists and their collaborators.

The ability of the ChAd3 Ebola virus vaccine to elicit rapid protection in monkeys is notable as the world health community battles an ongoing Ebola virus disease outbreak in West Africa. While the protective effects of the single shot waned over time, two out of four inoculated animals were protected when challenged with Ebola virus 10 months after vaccination.

The research team, headed by Nancy J. Sullivan, Ph.D., of the National Institute of Allergy and Infectious Diseases Vaccine Research Center, also demonstrated increased levels of durable protection using an additional vaccine. They inoculated four macaques first with the ChAd3 Ebola vaccine, then 8 weeks later with a booster vaccine containing Ebola virus gene segments incorporated into a different vector (a poxvirus).

Ten months after the initial inoculation, four out of four animals that received both shots were fully protected from infection with high doses of Ebola virus, demonstrating that the prime-boost regimen resulted in durable protection.

The research team included scientists from Okairos, a Swiss-Italian biotechnology company now part of GlaxoSmithKline, and the U.S. Army Medical Research Institute of Infectious Diseases. The experimental ChAd3 Ebola vaccine used in these non-human primate studies is the same one currently being tested in an early-stage human clinical trial at the NIH in Bethesda, Maryland.