Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection

Abstract

The persistence of symptoms in Lyme disease patients following antibiotic therapy, and their causes, continue to be a matter of intense controversy. The studies presented here explore antibiotic efficacy using nonhuman primates. Rhesus macaques were infected with B. burgdorferi and a portion received aggressive antibiotic therapy 4–6 months later. Multiple methods were utilized for detection of residual organisms, including the feeding of lab-reared ticks on monkeys (xenodiagnosis), culture, immunofluorescence and PCR. Antibody responses to the B. burgdorferi-specific C6 diagnostic peptide were measured longitudinally and declined in all treated animals. B. burgdorferi antigen, DNA and RNA were detected in the tissues of treated animals. Finally, small numbers of intact spirochetes were recovered by xenodiagnosis from treated monkeys. These results demonstrate that B. burgdorferi can withstand antibiotic treatment, administered post-dissemination, in a primate host. Though B. burgdorferi is not known to possess resistance mechanisms and is susceptible to the standard antibiotics (doxycycline, ceftriaxone) in vitro, it appears to become tolerant post-dissemination in the primate host. This finding raises important questions about the pathogenicity of antibiotic-tolerant persisters and whether or not they can contribute to symptoms post-treatment.

Citation: Embers ME, Barthold SW, Borda JT, Bowers L, Doyle L, et al. (2012) Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection. PLoS ONE 7(1): e29914. doi:10.1371/journal.pone.0029914

Editor: Jean Louis Herrmann, Hopital Raymond Poincare - Universite Versailles St. Quentin, France

Received: July 22, 2011; Accepted: December 6, 2011; Published: January 11, 2012

Copyright: © 2012 Embers et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by NIAID grant R01-AI042352 (MTP), R01-AI26815 (SWB and EH), a TNPRC Pilot Study Grant (MEE), and NCRR grant RR00164. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

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Introduction

Lyme borreliosis is caused by the spirochetes of the Borrelia burgdorferi sensu lato species complex. The clinical progression of Lyme borreliosis may be divided into early-localized, early-disseminated, and late stages. During the early-localized phase, the disease's most prevalent sign is an erythematous skin rash known as erythema migrans. Subsequently, patients may develop early-disseminated disease with dermatologic, rheumatologic, cardiac, and neurologic involvement. Patients with late disease present chiefly with arthritis or with neurologic manifestations [1]. The Infectious Diseases Society of America (IDSA) has issued guidelines for Lyme borreliosis therapy [2]. Signs and symptoms are usually successfully ameliorated with antimicrobial therapy. However, some patients continue to have persistent subjective complaints [3], [4] while a few patients fail to respond to antibiotic therapy, as made evident by signs of persistent infection [2], [5]. The response to treatment in patients with late manifestations is typically slower [2] and sometimes remains incomplete.

Post-treatment Lyme disease syndrome (PTLDS) is a condition that occurs in some patients after treatment for Lyme borreliosis. The cause of PTLDS is currently unknown but prolonged antibiotic therapy does not seem to be helpful [6], [7]. Objective evaluation of this phenomenon in humans is complicated by the difficulty in obtaining a patient population with confirmed Lyme borreliosis treated post-dissemination, and the vague, non-specific symptoms (fatigue, headache, memory and concentration difficulties, myalgias and arthralgias) with which PTLDS patients present. In addition, reliable procedures to determine that infection has been cleared from Lyme disease patients have not been established.

The C6 ELISA detects antibodies to a region of the B. burgdorferi VlsE lipoprotein that is immunogenic in infected individuals and common to all infectious variants tested thus far. Not only is the C6 test among the most reliable in terms of accuracy, but it is also a serologic test for Lyme disease that has been used experimentally as a predictor of treatment outcome [8]. In patients with PTLDS, anti-C6 titers were found to generally persist at a low level compared to acute patient titers [9]. To date, the experimental assessment, in animals, of antibiotic treatment effectiveness, measured by the presence or absence of spirochetes, correlated with C6 serologic test reactivity has not been reported.

Signs and symptoms of putative failure of antibiotic treatment in late disease or ineffectiveness of repeated treatment in patients with PTLDS may be formally attributed to several causes, including: 1) spirochetes that persist in the tissues, likely in small numbers, inaccessible or impervious to antibiotic; 2) inflammatory responses to residual antigens from dead organisms; or 3) autoimmune responses, possibly elicited by antigenic mimicry [10].

In an effort to gain insight into the viability of these hypotheses, we designed two experiments in which we respectively assessed the efficacy of two regimens of ceftriaxone and/or doxycycline treatment in rhesus macaques commencing at 4–7 months of infection with B. burgdorferi. Rhesus macaques were chosen because of the ability of this animal model to reproduce many of the key signs of human Lyme disease, including neuroborreliosis [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22] and because of the similarity between the available pharmacokinetics data for ceftriaxone and doxycycline in rhesus macaques and in humans [23], [24], [25], [26]. Our results confirm that spirochetes are capable of persisting in treated nonhuman primate hosts. We discuss the possible mechanisms and need for further inquiry into this phenomenon.

Results

We performed two separate experiments to assess post-treatment persistence by B. burgdorferi in nonhuman primates with treatment administered at different phases of disseminated infection. Both experiments involved infection, treatment post-dissemination, serology and detection of spirochetes in tissues. The two varied in the number of animals, B. burgdorferi strain used, time interval prior to treatment, antibiotic treatment regimen, and detection methods. The first (Experiment 1) was aimed at evaluating animals treated at the late disseminated phase of infection and the treatment regimen was chosen to correspond to the regimen used to treat human PTLDS patients in a clinical evaluation of treatment for this population [6]. The outline for Experiment 1 is depicted in Figure 1.

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Figure 1. Experimental design for assessment of treatment efficacy in the late, disseminated phase of infection (Experiment 1).
A) diagram of animal groups, showing inoculation (B. burgdorferi or sham) and treatment groups (treated with antibiotics or untreated); and B) the time line of the study.
doi:10.1371/journal.pone.0029914.g001

 

Full article : http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029914

 

 

A new theory on MS (angioplasty procedure)

Lauran Neergaard
THE ASSOCIATED PRESS

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WASHINGTON (AP) — Under intense pressure from patients, some U.S. doctors are cautiously testing a provocative theory that abnormal blood drainage from the brain may play a role in multiple sclerosis — and that a surgical vein fix might help.

If it pans out, the approach suggested by a researcher in Italy could mark a vast change for MS, a disabling neurological disease long blamed on an immune system gone awry. But many patients frustrated by today's limited therapies say they don't have time to await the carefully controlled studies needed to prove if it really works and are searching out vein-opening treatment now — undeterred by one report of a dangerous complication.

"This made sense and I was hell-bent on doing it," says Nicole Kane Gurland , the first to receive the experimental treatment at Washington's Georgetown University Hospital, which is set to closely track how a small number of patients fare before and after using a balloon to widen blocked veins.

In Buffalo, N.Y., more than 1,000 people applied for 30 slots in a soon-to-start study of that same angioplasty procedure. When the University at Buffalo team started a larger study a few months ago just to compare whether bad veins are more common in MS patients than in healthy people — not to treat them — more than 13,000 patients applied.

The demand worries Georgetown neurologist Dr. Carlo Tornatore, who teamed with vascular surgeon Dr. Richard Neville in hopes of getting some evidence to guide his own patients' care.

"A lot of people are starting to go to fly-by-night places," says Tornatore. Doing this research takes time, he said. "It's a marathon, not a 100-yard (90-meter) sprint. We have to be very careful."

Multiple sclerosis occurs when the protective insulation, called myelin, that coats nerve fibers gradually is destroyed and scar tissue builds up, short-circuiting messages from the brain and spinal cord to the rest of the body — impairing walking and causing fatigue and vision, speech, memory and other problems. It affects about 2.5 million people worldwide.

A condition with an unwieldy name has become the hottest topic of debate in MS: Chronic cerebrospinal venous insufficiency, or CCSVI. An Italian vascular specialist, Dr. Paolo Zamboni, was hunting ways to help his wife's MS when he discovered that veins carrying oxygen-depleted blood down the neck or spinal cord were narrowed, blocked or twisted in a group of patients. Zamboni reported that made blood back up in a way that might be linked to MS' damage, by causing tiny leaks of immune cells into the brain that start a cascade of inflammatory problems.

Then came the step that spread excitedly through MS patient Internet forums: In a pilot study, Zamboni's team used balloon angioplasty — similar to a longtime method for unclogging heart arteries — to widen affected veins in 65 patients. He reported varying degrees of improvement, mostly in patients with the relapsing-remitting form of MS who experienced fewer flare-ups of symptoms over the next 18 months and some improvements in quality of life.

But nearly half had their veins relapse, and Zamboni urged a larger, more scientifically controlled study be done.

Next, Buffalo researchers scanned the veins of 500 people. About 55 percent of MS patients had signs of CCSVI, compared with 22 percent of healthy people, says lead researcher Dr. Robert Zivadinov, who will present his data next month at a major neurology meeting.

Meanwhile, a Stanford University surgeon tried implanting scaffolding-like stents — also developed for heart disease — into some MS patients' narrowed veins. Dr. Michael Dake halted the work in December after 35 people were treated, saying in an e-mail to colleagues that he decided "after deep soul-searching" not to continue outside of a clinical trial. Stanford won't discuss details, but the journal Annals of Neurology reported that one patient's stent dislodged and flowed to the heart, requiring emergency open-heart surgery to remove it. (An earlier death was reported by family members to be from a stroke unrelated to the MS treatment.)

The MS Society soon will announce funding for additional studies.

Like many neurologists, Georgetown's Tornatore watched the developments with a mixture of skepticism and curiosity. After all, decades ago some doctors first suggested circulation might play a role. The scars tend to cluster near veins, and blood-thinning treatment was tried before immune-targeting drugs were proven to help many MS patients.

He ticks off the possibilities: This could be a blind alley, like so many to befall MS over the years. Or it could work a little. Or it might be revolutionary.

"I have no idea. I'm not predisposed to any of them," Tornatore says.

But he and Neville decided angioplasty was the least risky option for a limited test. In 30 patients who've undergone a $400 ultrasound exam so far, about half have evidence of the vein abnormality.

Gurland was the first treated earlier this month, her jugular veins blocked so tightly that Neville had a hard time even pushing the tiny angioplasty wire inside. But right after the treatment, Gurland's feet that for years had been cold and purplish became warmer and normally colored.

What about MS' hallmark fatigue and weakness, and her scarred nerve cells? While Gurland thinks her balance in the morning, often her worst time, is improving a bit, it's too soon to know; those tests are yet to come.

But last week, her close friend Heather Puck, 61, came in for a vein check, too — calling it the first MS test she ever hoped to pass.

Study explores link between sunlight, multiple sclerosis

Hector DeLuca
University of Wisconsin-Madison
23 Mar 2010

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Madison - For more than 30 years, scientists have known that multiple sclerosis (MS) is much more common in higher latitudes than in the tropics. Because sunlight is more abundant near the equator, many researchers have wondered if the high levels of vitamin D engendered by sunlight could explain this unusual pattern of prevalence.

Vitamin D may reduce the symptoms of MS, says Hector DeLuca, Steenbock Research Professor of Biochemistry at University of Wisconsin-Madison, but in a study published in PNAS this week, he and first author Bryan Becklund suggest that the ultraviolet portion of sunlight may play a bigger role than vitamin D in controlling MS.

Multiple sclerosis is a painful neurological disease caused by a deterioration in the nerve's electrical conduction; an estimated 400,000 people have the disabling condition in the United States. In recent years, it's become clear the patients' immune systems are destroying the electrical insulation on the nerve fibers.

The ultraviolet (UV) portion of sunlight stimulates the body to produce vitamin D, and both vitamin D and UV can regulate the immune system and perhaps slow MS. But does the immune regulation result directly from the UV, indirectly from the creation of vitamin D, or both?

The study was designed to distinguish the role of vitamin D and UV light in explaining the high rate of MS away from the equator, says DeLuca, a world authority on vitamin D.

"Since the 1970s, a lot of people have believed that sunlight worked through vitamin D to reduce MS," says DeLuca. "It's true that large doses of the active form of vitamin D can block the disease in the animal model. That causes an unacceptably high level of calcium in the blood, but we know that people at the equator don't have this high blood calcium, even though they have a low incidence of MS. So it seems that something other than vitamin D could explain this geographic relationship."

Using mice that are genetically susceptible to MS-like disease, the researchers triggered the disease by injecting a protein from nerve fibers. The researchers then exposed the mice to moderate levels of UV radiation for a week. After they initiated disease by injecting the protein, they irradiated the mice every second or third day.

The UV exposure (equivalent to two hours of direct summer sun) did not change how many mice got the MS-like disease, but it did reduce the symptoms of MS, especially in the animals that were treated with UV every other day, DeLuca says.

The research group also found that although the UV exposure did increase the level of vitamin D, that effect, by itself, could not explain the reduced MS symptoms.

In some situations, radiation does reduce immune reactions, but it's not clear what role that might play in the current study. "We are looking to identify what compounds are produced in the skin that might play a role, but we honestly don't know what is going on," DeLuca says. "Somehow it makes the animal either tolerate what's going on, or have some reactive mechanism that blocks the autoimmune damage."

MS is a progressive neurological disease with few effective treatments, but DeLuca stresses that the study, however hopeful, may or may not lead to a new mode of treatment. "There are several ways this could go. If we can find out what the UV is producing, maybe we could give that as a medicine. In the short term, if we can define a specific wavelength of light that is active, and it does not overlap with the wavelengths that cause cancer, we could expose patients who have been diagnosed with MS to that wavelength."

Does this information change the common prescription to avoid excessive sun exposure? "If you have an early bout with MS, then you have to think about your options," says DeLuca. "Remember, this is just experimental work at this stage. Whether it can be translated into practical applications on MS remains to be seen."

Brain Blood Vessels Clue to Multiple Sclerosis

BBC News
Wed, 10 Feb 201



More than 55% of multiple sclerosis patients have been found to have constricted blood vessels in their brains, a US study says.

The preliminary results are from the first 500 patients enrolled in a trial at the University of Buffalo.

The abnormality was found in 56.4% of MS patients and also in 22.4% of healthy controls.

The MS Society said it was intriguing but not proof that this caused MS - as one leading expert claims.

Testing theory

The New York researchers were testing a theory from Italian researcher, Dr Paolo Zamboni who claims that 90% of MS is caused by narrowed veins.

He says the restricted vessels prevent the blood from draining fast enough and injure the brain by causing a build up of iron which leads to MS.

He has already widened the blockages in a handful of patients including his wife.

MS is a long-term inflammatory condition of the central nervous system which affects the transfer of messages from the nervous system to the rest of the body.

The Buffalo team used Doppler ultrasound to scan the patients in different body postures to view the direction of venous blood flow.

The 500 MS patients, both adults and children, also underwent MRI scans of the brain to measure iron deposits in surrounding areas of the brain.

The full results will be presented at an American neurology conference in April.

There were 161 healthy controls.

'Cautious optimism'

Robert Zivadinov who led the study at the University of Buffalo, said he was "cautiously optimistic and excited" about the preliminary data.

"They show that narrowing of the extracranial veins, at the very least, is an important association in multiple sclerosis.

"We will know more when the MRI and other data collected in this study are available."

Dr Doug Brown, Biomedical Research Manager at the MS Society, said: "These results are intriguing but it is important to remember that although people with MS may show evidence of chronic cerebrospinal venous insufficiency in screening studies, there's no proof as yet that this phenomenon is a cause of MS, nor that treating it would have an effect on MS.

"The next step is to determine what this actually means for MS and an investigation into whether there's any potential therapeutic benefit from treatment will be pivotal for this novel theory."
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Key Mechanism in Development of Nerve Cells Found

ScienceDaily
Wed, 30 Sep 2009
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Chaos brews in the brains of newborns: the nerve cells are still bound only loosely to each other. Under the leadership of Academy Research Fellow Sari Lauri, a team of researchers at the University of Helsinki has been studying for years how a neural network capable of processing information effectively is created out of chaos. The team has now found a new kind of mechanism that adjusts the functional development of nerve cell contacts.

The results were published in early September as the leading article of the Journal of Neuroscience.

The work carried out by Lauri's team and its partners at the Viikki campus sheds light on a development path that results in some of the large number of early synapses becoming stronger. The researchers found out hat the BDNF growth factor of nerve cells triggers a functional chain which promotes the release of the neurotransmitter glutamate. BDNF enables the release of glutamate by prohibiting the function of kainate receptors which slow down the development of the preforms of the synapses. The activity of the kainate receptors restricts the release of glutamate and the development of synapses into functional nerve cell contacts.

It is noteworthy that the brain of a newborn itself seems to organise its own development. The electrical activity of the waking brain triggers the series of events controlled by the BDNF protein, as a result of which kainate receptor activity disappears in some synapses. The development is based on the considerable plasticity of the developing neural network: it can reshape its structureand function to a large extent.

According to Lauri, the new research results help understand how central nervous system diseases originating in early development are established. The finding also provides researchers with the opportunity to obtain information about the different aspects of endogenous activity of the brain. At the same time, it could be possible to develop new kinds of pharmaceuticals for the treatment of childhood epilepsy, for example.

Lauri's team conducted the research in co-operation with the research teams of Eero Castren and Tomi Taira from the Neuroscience Centre, and the research team of Jari Yli-Kauhaluoma from the Faculty of Pharmacy.

Scientists Make Paralyzed Rats Walk Again After Spinal-Cord Injury

Medical News Today
Mon, 21 Sep 2009

UCLA researchers have discovered that a combination of drugs, electrical stimulation and regular exercise can enable paralyzed rats to walk and even run again while supporting their full weight on a treadmill.

Published Nov. 20 in the online edition of Nature Neuroscience, the findings suggest that the regeneration of severed nerve fibers is not required for paraplegic rats to learn to walk again. The finding may hold implications for human rehabilitation after spinal cord injuries.

"The spinal cord contains nerve circuits that can generate rhythmic activity without input from the brain to drive the hind leg muscles in a way that resembles walking called 'stepping,'" explained principal investigator Reggie Edgerton, a professor of neurobiology and physiological sciences at the David Geffen School of Medicine at UCLA.

"Previous studies have tried to tap into this circuitry to help victims of spinal cord injury," he added. "While other researchers have elicited similar leg movements in people with complete spinal injuries, they have not achieved full weight-bearing and sustained stepping as we have in our study."

Edgerton's team tested rats with complete spinal injuries that left no voluntary movement in their hind legs. After setting the paralyzed rats on a moving treadmill belt, the scientists administered drugs that act on the neurotransmitter serotonin and applied low levels of electrical currents to the spinal cord below the point of injury.

The combination of stimulation and sensation derived from the rats' limbs moving on a treadmill belt triggered the spinal rhythm-generating circuitry and prompted walking motion in the rats' paralyzed hind legs.

Daily treadmill training over several weeks eventually enabled the rats to regain full weight-bearing walking, including backwards, sideways and at running speed. However, the injury still interrupted the brain's connection to the spinal cord-based rhythmic walking circuitry, leaving the rats unable to walk of their own accord.

Neuro-prosthetic devices may bridge human spinal cord injuries to some extent, however, so activating the spinal cord rhythmic circuitry as the UCLA team did may help in rehabilitation after spinal cord injuries.

The study was funded by the Christopher and Dana Reeve Foundation, Craig Nielsen Foundation, National Institute of Neurological Disorders and Stroke, U.S. Civilian Research and Development Foundation, International Paraplegic Foundation, Swiss National Science Foundation and the Russian Foundation for Basic Research Grants.

Antioxidant Controls Spinal Cord Development

PhysOrg
Fri, 18 Sep 2009 13:55 UTC

Researchers at the Johns Hopkins School of Medicine have discovered how one antioxidant protein controls the activity of another protein, critical for the development of spinal cord neurons. The research, publishing this week in Cell, describes a never-before known mechanism of protein control.

"This is the first time we've seen this type of chemical reaction control neuronal differentiation," says Shanthini Sockanathan, Ph.D., an associate professor at the Johns Hopkins Solomon H. Snyder Department of Neuroscience. "And it's probably not specific for motor neurons that we study, but also for development of a wide variety of neurons."

Previous research had shown that the GDE2 protein can cause immature cells in the spinal cord to differentiate into motor neurons, the nerve cells that connect to and control muscle contraction. Too little GDE2 causes motor neurons to not develop, while too much GDE2 causes them to develop too quickly, depleting progenitor pools.

"We reasoned that there must be tight control of GDE2 so we set out to look for the regulator by looking for other proteins that can bind to GDE2," says Sockanathan.

Using biochemical approaches to isolate all proteins that normally bind to GDE2 in the developing spinal cord, followed by proteomic analysis to identify all binding proteins, the research team found a few hundred proteins. One, Prdx1, had been reported by others to have tumor-suppressing abilities, which caught Sockanathan's eye for further investigation.

The team first asked if the Prdx1 protein can affect motor neuron development by removing it from developing spinal cords of chick embryos. Embryos lacking Prdx1 showed loss of motor neurons similar to that seen in embryos lacking GDE2, suggesting that indeed Prdx1 is somehow involved in motor neuron development.

To figure out how Prdx1 and GDE2 interact to cause immature cells to develop into motor neurons, the team mutated the proteins and examined how the mutations affect the cells. Mutations that prevent the two proteins from binding resulted in no motor neurons. Similarly, mutations that disrupt the enzyme abilities of GDE2 and Prdx1 also resulted in no motor neurons. In fact, only when GDE2 and Prdx1 can bind each other and work as enzymes do motor neurons develop.

"So we thought maybe the antioxidant enzyme activity of Prdx1 is doing something to regulate GDE2 function," says Sockanathan. Her team then looked into what already was known about Prdx1's enzyme activity. They found that bacteria and yeast versions of Prdx1 are able to help alter certain chemical bonds in proteins that form between specific amino acids that contain so-called sulfhydryl or "-SH" groups.

That led them to reexamine the GDE2 protein for sulfhydryl groups. As it turns out, they found 4 in GDE2: Three are close together and one is clear on the other end of the protein. They first performed some biochemistry experiments to determine whether these sulfhydryl groups can form disulfide bonds - they can. Then, two at a time, the researchers engineered mutations to replace each -SH-containing amino acid in GDE2 and asked if the mutated protein could still bind to Prx1. They found one combination of mutations that did not behave the same as the unmutated control, leading them to conclude that Prx1 must break the chemical bond between those two specific amino acids.

"We think that Prx1 breaks this bond in GDE2, activating it to promote motor neuron differentiation," says Sockanathan. "This suggests a new general control mechanism that regulates when cells divide and when they differentiate. We're excited to see how widespread it might be."

Découverte de deux gènes qui aident à combattre la sclérose en plaque

ouest-france
01:04 - samedi 12 septembre 2009

Des chercheurs américains ont découvert deux gènes impliqués dans la restauration du système nerveux central de souris atteintes de sclérose en plaque. Cette découverte offre un nouvel espoir pour mettre au point des thérapies plus efficaces et prédire la façon dont les patients répondront à cette maladie auto-immune dégénérative.

L'équipe d'Allan Bieber, spécialiste des neurosciences à la clinique Mayo dans le Minnesota, a étudié des souris atteintes d'une forme chronique de maladie évolutive assimilée à la sclérose en plaque et a cartographié les gènes de celles qui ont spontanément réparé les dommages causés par la maladie. Les chercheurs ont découvert deux facteurs génétiques déterminants dans cette évolution positive

Stem cells could save stroke victims

John von Radowitz
The Independent
Mon, 09 Mar 2009

Disabling strokes could one day be treated by replacing damaged brain tissue with stem cells, scientists have shown.

Researchers used a new technique to insert therapeutic stem cells into the brains of rats with pinpoint accuracy.

Once implanted the cells began to form new brain tissue and nerve connections.

The work is at an early stage and does not yet prove that stroke symptoms such as paralysis can be reversed.

But it demonstrates that lost brain tissue can be replaced with stem cells targeted at sites of damage.

Stem cells are immature cells with the ability to take on any of a number of specialist roles.

In previous animal experiments, stem cells implanted into the brain have tended to migrate to surrounding healthy tissue rather than fill up the hole left by a stroke.

Scientists from King's College London and the University of Nottingham overcame the problem by loading the cells onto biodegradable particles.

These were then injected through a fine needle to the precise site of damage, located using a magnetic resonance imaging (MRI) scanner.

Once implanted, the particles disappeared leaving gaps for the growth of new tissue and nourishing blood vessels.

The cells, derived from stem cells taken from mouse embryos, had already progressed some of the way to becoming neurons.

They were attached to particles made from a biodegradable plastic-like polymer called PLGA.

Dr Mike Modo, leading the King's College team from the university's Institute of Psychiatry, said: "The stem cell-loaded PLGA particles can be injected through a very fine needle and then adopt the precise shape of the cavity. In this process the cells fill the cavity and can make connections with other cells, which helps to establish the tissue.

"Over a few days we can see cells migrating along the scaffold particles and forming a primitive brain tissue that interacts with the host brain. Gradually the particles biodegrade leaving more gaps and conduits for tissue, fibres and blood vessels to move into."

Colleague Kevin Shakesheff, Professor of Advanced Drug Delivery and Tissue Engineering at the University of Nottingham, said: "This was a great collaborative project with the Kings College team and hopefully this technology will be taken to the clinical setting soon. Repairing damaged brain tissue is one of the ultimate challenges in medicine and science. It is great that we are now one step closer to achieving that goal."

The next stage will be to apply a "growth factor" chemical called VEGF with the particles to encourage the creation of new blood vessels.

The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC), is reported in the journal Biomaterials.

Strokes occur when part of the brain dies off because of a blocked or burst blood vessel.

An estimated 150,000 strokes occur in the UK each year, 67,000 of which are fatal.

Strokes cause more disability than any other chronic condition. Around 300,000 people in the UK are moderately or severely disabled because of a stroke.

Joe Korner, from the Stroke Association charity, said: "This research is another step towards using stem cell therapy in treating and reversing the brain damage caused by stroke. It is exciting because researchers have shown they are able to overcome some of the many challenges in translating the potential of using stem cells into reality.

"The potential to reverse the disabling effects of stroke seems to have been proved. However the development of stem cell therapy for stroke survivors is still in the early stages and much more research will be needed before it can be tested in humans or used in practice.

"Every five minutes someone in the UK has a stroke and it is vital that we do all we can to help those affected by stroke."

Professor Douglas Kell, chief executive of the BBSRC, said: "Stroke is a leading cause of disability in industrialised countries. It is reassuring to know that the technology for treating stroke by repairing brain damage is getting ever closer to translation into the clinic. This crucial groundwork by Dr Modo and his colleagues will surely be a solid foundation of basic research for much better treatments in the future."

Anthony Hollander, Professor of Rheumatology and Tissue Engineering at the University of Bristol, said: "We are only just beginning to understand how to use tissue engineering to cure diseases. This study shows the exciting possibility of using a biomaterial to deliver stem cells to a very specific location in the brain. It is too early to say if it will be clinically effective in patients but the more we explore these possibilities the more likely it is that we will develop successful therapies."

Two distinct molecular pathways can make regulatory immune cells

Finding a way to bypass the molecular events involved in autoimmunity - where the body's immune system mounts a self-directed attack - could lead to new treatments for autoimmune disorders and chronic infections. A study published in this week's issue of PLoS Biology describes genetic evidence that two distinct molecular pathways control the formation of regulatory T cells (Treg), a cell type vitally important in limiting undesirable immune responses.

Treg cells are like the peace-keepers of the immune defence system - they limit the actions of effector T cells, the foot-soldiers of the body. If the body lacks sufficient numbers of Treg cells, it loses the ability to tone down immune responses once invading pathogens are cleared. In addition, the body is unable to suppress T cell responses that recognize and target the body itself. The latter can lead to autoimmunity, which can destroy vital tissues and organs.

Under normal healthy conditions, the majority of Treg cells are derived from an organ called the thymus. New work from researchers at Cincinnati Children's Hospital Medical Center and The Scripps Research Institute in California, shows that if a gene called Carma1 isn't expressed normally, Treg development is impaired in the thymus. Mutations in Carma1 can result in a failure of the thymus to produce Treg cells, said senior investigator Kasper Hoebe, Ph.D., a researcher at Cincinnati.

But the study also points to a second molecular pathway - occurring in the peripheral lymphoid system - that is known to result in development of Treg cells. This means if the process in the thymus breaks down, as in the case with Carma1 mutations, Treg cells created in the peripheral lymphoid system can compensate.

"We show that the two pathways for Treg development are molecularly distinct, and Treg can arise quite well in the peripheral lymphoid system, via mechanisms that are independent of the thymic process," Dr. Hoebe said. "This is important because it shows the flexibility of the immune system to regulate T cell responses. If we understand the molecular requirements of these pathways we can potentially use these as targets for therapeutic intervention - which is the eventual goal."

Possible therapies may include the ability to repress the self-destructive immune response in autoimmune disease by increasing Treg development, or achieving the opposite effect to treat chronic infectious diseases - inhibiting Treg development and promoting activation of destructive T cells.

More information: Barnes MJ, Krebs P, Harris N, Eidenschenk C, Gonzalez-Quintial R, et al. (2009) Commitment to the regulatory T cell lineage requires CARMA1 in the thymus but not in the periphery. PLoS Biol 7(3): e1000051. doi:10.1371/journal.pbio.1000051, http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.1000051

Source: Public Library of Science

Obtention de cellules souches neuronales

Des chercheurs de l'Université (Une université est un établissement d'enseignement supérieur dont l'objectif est la production du savoir (recherche),...) de Bonn ont réussi à obtenir des cellules souches neuronales à partir de cellules souches embryonnaires humaines.

Ces cellules présentent l'intérêt non seulement de pouvoir se conserver presque sans limite dans une culture (La définition que donne l'UNESCO de la culture est la suivante [1] :), mais également de servir de source presque inépuisable pour différents types de cellules nerveuses. Cette recherche (La recherche scientifique désigne en premier lieu l’ensemble des actions entreprises en vue de produire et de...) a aussi permis de démontrer que ces cellules nerveuses peuvent s'intégrer dans les circuits neuronaux du cerveau.

L'étude est publiée dans la prochaine édition de Proceedings of the National Academy of Sciences PNAS (doi: 10.1073/pnas.0808387106).


Pendant des années, la recherche sur les cellules souches a semblé divisée en deux mondes: les cellules sources embryonnaires au développement illimité d'une part, et les cellules souches somatiques qui peuvent être obtenues à partir de tissus d'adultes, mais ces dernières cellules étaient limitées dans leur potentiel de développement.

Les scientifiques de l'Université de Bonn ont rapproché ces deux mondes en créant des cellules souches du cerveau pouvant se multiplier et se conserver quasiment indéfiniment. C'est à partir de ces cellules que les chercheurs ont pu obtenir différentes cellules nerveuses dont des semblables à celles observées dans la maladie de Parkinson.

L'expérimentation (L'expérimentation est une méthode scientifique qui consiste à tester par des expériences répétées la validité d'une...) sur des animaux a prouvé que ces cellules nerveuses obtenues artificiellement fonctionnaient bien. Les cellules transplantées sur des souris de laboratoire sont entrées en contact avec le cerveau du receveur pouvant émettre des signaux et en recevoir. Les chercheurs veulent utiliser cette source quasi inépuisable de cellules nerveuses humaines pour faire des études sur les maladies neuro-dégénératives.

Source: communiqué de presse de l'Université de Bonn
Illustration: Wikipédia

Turning down gene expression promotes nerve cell maintenance

February 2nd, 2009

Anyone with a sweet tooth knows that too much of a good thing can lead to negative consequences. The same can be said about the signals that help maintain nerve cells, as demonstrated in a new study of myelin, a protein key to efficient neuronal transmission.

Normal nerve cells have a myelin sheath, which, much like the insulation on a cable, allows for rapid and efficient signal conduction. However, in several diseases - the most well-known being multiple sclerosis - demyelination processes cause the breakdown of this "insulation", and lead to deficits in perception, movement, cognition, etc. Thus, in order to help patients of demyelinating disease, researchers are studying the pathways that control myelin formation and maintenance.

A new study by University of California scientists examines the role of a structural protein, called lamin, in maintaining myelin. They found that, while lamin is necessary in the initial stages of myelin formation, too much lamin promotes myelin breakdown. Further investigation led the researchers to the discovery of a signal that fine-tunes lamin expression. This signal, a microRNA called miR-23, can turn down lamin gene expression, and thereby prevent demyelination due to lamin overexpression.

This new work reported in Disease Models & Mechanisms (DMM), adds another piece to the puzzle that is understanding myelin formation and maintenance. Additionally, the identification of miR-23 as a myelin regulator introduces a new potential drug target in developing treatments for demyelinating illness.

The report was written Shu-Ting Lin and Ying-Hui Fu at the Department of Neurology, University of California San Francisco. The report is published in the March/April issue of Disease Models & Mechanisms (DMM), a research journal published by The Company of Biologists, a non-profit based in Cambridge, UK.

Un remède anti-leucémie stoppe et inverse les effets de la sclérose

AFP 23/10/2008

LONDRES (AFP) — Un médicament, développé à l'origine pour traiter la leucémie, peut stopper voire inverser les effets débilitants de la sclérose en plaques (SEP), ont annoncé des chercheurs de l'Université de Cambridge.

Au cours des essais, l'alemtuzumab a réduit le nombre d'attaques chez les malades et leur a aussi permis de récupérer des fonctions perdues, en permettant apparemment au tissu cérébral de se réparer, de sorte que des individus étaient moins handicapés à la fin qu'au début de l'étude, selon ces chercheurs.

"La possibilité qu'un traitement contre la SEP favorise la reconstitution du tissu cérébral est sans précédent", a affirmé le Dr Alasdair Coles, enseignant au département de neurosciences cliniques de Cambridge, qui a coordonné une partie de l'étude, publiée dans le New England Journal of Medecine.

"Nous sommes en présence d'un médicament qui, s'il est administré suffisamment tôt, pourrait efficacement stopper l'avancée de la maladie et également rétablir des fonctions perdues en favorisant la reconstitution du tissu cérébral endommagé", a-t-il expliqué.

La MS Society, la plus importante organisation caritative britannique consacrée au soutien des personnes atteintes de SEP, s'est dit "ravie" des résultats de l'étude.

"C'est le premier médicament qui a montré un potentiel pour arrêter et même inverser les effets débilitants de la SEP", s'est réjoui le chef de la recherche de la MS Society, Lee Dunster.

"Des travaux supplémentaires sont nécessaires pour prouver l'effet à long terme de ce traitement et nous attendons avec impatience les résultats de la prochaine étape - déjà en cours - de cette importante recherche", a-t-il poursuivi.

La SEP est une maladie incurable du système nerveux central qui touche 2,5 millions de personnes dans le monde.

Cette infection inflammatoire provoque la destruction de la myéline, une substance entourant les nerfs et assurant la transmission rapide de l'influx nerveux. Elle conduit à des handicaps plus ou moins lourds, notamment pertes de vision, de mobilité, troubles cognitifs.

L'étude sur trois ans a porté sur 334 patients souffrant d'une forme rémittente de SEP à un stade précoce qui n'avait pas été traité auparavant. Un groupe a reçu de l'alemtuzumab, un autre un médicament contre la SEP, l'interferon beta-1a.

L'alemtuzumab a permis une réduction plus importante que l'autre médicament du nombre d'attaques et du risque de handicaps durables.

Plusieurs individus du premier groupe ont également récupéré certaines fonctions perdues alors que les handicaps des patients du second groupe ont empiré, selon l'étude.

Leukemia drug improves multiple sclerosis symptoms in some people

Nathan Seppa
Web edition : Wednesday, October 22nd, 2008

A disease thought to be incurable is now a step closer to losing that dispiriting reputation. Multiple sclerosis, the disabling neuromuscular disease that has resisted effective drug therapy, eases off in some people given a drug normally prescribed for leukemia, researchers report in the Oct. 23 New England Journal of Medicine.

“More than half the patients in this study actually improved a significant amount” when taking the drug alemtuzumab, says study coauthor David Margolin, a neurologist at Genzyme Corp. in Cambridge, Mass., which teamed with an international team of researchers in conducting the trial. “We think this is something very special.”

That optimism is tempered by worrisome side effects that showed up in MS patients taking the drug. Two more large-scale trials of MS patients are now getting under way to address those issues and confirm the positive findings.

In MS, the body’s own immune cells orchestrate an attack on myelin, the fatty sheaths that insulate nerve fibers in the central nervous system. The origins of this mutiny remain a medical mystery, but the disaster that follows is well documented: A torrent of inflammation robs the nerves of their protective myelin, disrupting nerve signals and resulting in the motor control losses that mark MS. In the early stages, MS attacks often come and go in relapsing-and-remitting fashion. In the worst case scenario, the autoimmune assault becomes chronic, leading to irreparable nerve damage and permanent disability.

Enter alemtuzumab, also called Campath. This drug targets a compound called CD52, which appears on T cells and B cells, the prime movers of the immune system. Alemtuzumab works well, killing off nearly all the T and B cells, and thus wiping out a huge portion of a person’s immune system. That’s a good thing if your immune cells are running amok, as in autoimmune disease or leukemia. But it can leave a person vulnerable to infection.

Fortunately, this housecleaning is temporary. Since nascent T and B cells don’t make CD52, they escape the purge and go on to repopulate the immune system anew. That takes a few months for B cells but years for T cells, says study coauthor Alisdair Coles, a neurologist at the University of Cambridge in England.

While the drug has helped patients fight chronic lymphocytic leukemia, testing against MS progressed slowly in the 1990s as researchers mainly tested alemtuzumab in advanced-stage, mostly middle-aged MS patients, with little success.

That approach changed in 2002 when an international team of researchers began testing the drug on younger, less-advanced-stage MS patients over the course of a three-year trial. The scientists enrolled people mainly in their 20s and 30s with MS that was diagnosed only 1.3 years earlier, on average, and who hadn’t been treated for the condition yet.

The researchers randomly assigned 111 to get interferon beta 1a, a standard MS drug given as three injections per week. Another 223 patients received alemtuzumab, delivered in a series of intravenous infusions over five days once a year. Most volunteers getting alemtuzumab got two series of infusions, one at the outset and another after 12 months; 46 received a third course a year after that.

The interferon group was slated to receive regular injections during the three-year trial, but two-fifths stopped taking the drug at some point, most complaining of side effects or lack of effectiveness. All patients were monitored for three years.

Clinical testing showed that disabilities for people on interferon rose on average during the trial but fell in those getting alemtuzumab, a first for a large trial, the authors point out.

Overall, 57 percent of those on alemtuzumab improved during the study, while roughly one-fifth worsened and the others held steady. Of those getting interferon, one-third improved, 41 percent declined and the rest held even.

Over the three years, only 20 percent of the alemtuzumab patients had a relapse, compared with 48 percent of the interferon patients.

What’s more, magnetic resonance imaging, or MRI, of the patients’ brains showed less inflammation in those getting alemtuzumab. The brain can wither in MS patients. Between months 12 and 36 in this study, interferon patients experienced a slight loss of brain volume on average whereas alemtuzumab patients added volume.

Combined, these findings suggest that the drug is somehow promoting brain repair in MS patients. “This is unprecedented. It hasn’t been seen before,” says Coles. “Up until now, no one would have thought this would happen.” He was particularly surprised by the MRI data. “Between 12 and 36 months,” he says, patients getting alemtuzumab “were actually acquiring new tissue in the brain.”

The most common side effect from alemtuzumab concerns the thyroid gland, and 23 percent of patients getting the drug in this trial developed thyroid problems. In some people, the gland becomes overactive; in others, it became underactive. Of those getting inferferon, 3 percent developed thyroid problems.

Immunologist Bibiana Bielekova of the National Institute of Neurological Disorders and Stroke in Bethesda, Md., says these thyroid problems are not always easy to treat. Plus, many patients with early-stage MS and mild symptoms might not relish the risk of developing a new problem, particularly when there are several other options available for treating their MS at that stage.

On the other hand, Margolin says, thyroid problems, if manageable, “might be a fair trade off” since they aren’t as serious as MS.

A dangerous bleeding disorder called ITP, or idiopathic thrombocytopenic purpura, showed up in 3 percent of alemtuzumab patients and 1 percent of interferon patients. ITP patients’ immune cells attack their own blood-clotting platelets, risking hemorrhage. One person on alemtuzumab died from the disorder.

“We are quite aware of how incredibly effective this drug is,” Bielekova says. “But everybody is scared to death of those side effects.”

Margolin says physicians will closely monitor patients’ platelet counts in the two upcoming trials of alemtuzumab.

Previous studies had gauged alemtuzumab’s effects against MS largely in patients who had late-stage disease. The drug showed promise, but patients still went downhill, Bielekova says.

Margolin suggests that using alemtuzumab to treat early-stage MS patients “who are still walking around” yields benefits because temporarily knocking out T cells and B cells quells the immune system’s ability to generate inflammation, an early-stage event in MS. “That seems to give the body a chance to recover,” he says.

The new findings are “remarkable,” says Stephen Hauser, a neurologist at the University of California, San Francisco, writing in the same NEJM issue. This and previous work pitting alemtuzumab against MS represent “thoughtful clinical investigations [that] have advanced the field substantially,” he says. But only long-term testing will establish alemtuzumab’s place in the anti-MS armamentarium, he says.

Response To Immune Protein Determines Pathology Of Multiple Sclerosis

Science Daily
Mon, 13 Oct 2008

New research may help reveal why different parts of the brain can come under attack in patients with multiple sclerosis (MS). According to a new study in mice with an MS-like disease, the brain's response to a protein produced by invading T cells dictates whether it's the spinal cord or cerebellum that comes under fire.

The study - from researchers at the University of Maryland School of Medicine in Baltimore and Washington University in St. Louis - will be published online on October 13th in the Journal of Experimental Medicine.

In most MS patients, the disease primarily affects the spinal cord and the white matter of the brain. But a small percentage of patients develop an atypical form of the disease, which primarily affects the cerebellum - the part of the brain that controls sensory perception and movement. For these patients, the disease tends to progress more rapidly and the prognosis is particularly bleak.

MS ensues when the body's T cells invade the brain and trigger nerve-damaging inflammation, in part by secreting proteins called cytokines. According to the new study, lead by Washington University scientist John Russell, the brain's response to one particular immune protein, called interferon-g (IFNg), determines which part of the brain the T cells attack. In mice that are oblivious to IFNg (because they lack its receptor), mice suffer cerebellum and brain stem inflammation, but their spinal cords are spared. When IFNg receptors were left intact, the reverse occurred.

Exactly how the brain's response to IFNg directs the T cell attack is not yet known, but the authors suspect that IFNg triggers a localized production of T cell-attracting proteins in the spinal cord. Translating the details of the "conversation" between T cells and brain cells, suggests Russell, might bring scientists closer to understanding the variable manifestations of human MS.

Dark-hued fruits, veggies are good for the brain (Les fruits de couleurs foncée, les légumes sont bon pour le cerveau)

Neuroscientist James A. Joseph is one of those lucky people who gets to have his cake and eat it, too. At the Human Nutrition Research Center on Aging at Tufts University (Medford, Massachusetts), Joseph revels in his research demonstrating that dark-hued fruits and vegetables, especially blueberries, are just about the best foods you could consume for inoculating brain and body against the ravages of time.

Every morning before heading to his Boston lab, Joseph pours himself a glass of ruby-red pomegranate juice and then chases it with roughly a cup of blueberries. Not just any blueberries but wild ones, flash-frozen to preserve the phytochemicals that research shows are particularly abundant in the tiny fruits that fend for themselves against the short growing season and harsh conditions of northern climates. There they stretch themselves across stony fields so inhospitable they're known as blueberry barrens.

At work, studying the nutritional modulation of cognitive decline, Joseph delineates the bioactive properties of the fruits he calls "brainberries." Yes, blueberries provide traditional nutrients - carbohydrates, fiber, vitamins C and E, manganese. But the deeply pigmented flavonoid phytochemicals known as anthocyanidins found in the fruit are not nutrients in the strict sense of the word. They are, however, biologically active in surprisingly sophisticated ways: intervening at the molecular level along signaling pathways to turn vital genes on or off in brain cells, making brain cells maximally responsive to incoming messages from other cells, even prompting the growth of new nerve cells.

Cumulatively, the berries produce antioxidant effects, neutralizing cellular damage created by free radicals of oxygen and blocking pathways by which oxidative stress damages cells. Perhaps more important, they function as anti-inflammatory agents to preserve cardiovascular as well as brain integrity. "Oxidative stress and inflammation are the evil twins of brain aging," Joseph insists.

Berries make a difference at the behavioral level, too. Aging rats fed the equivalent of a cup of berries a day navigate water mazes like pups, with few mistakes of memory. Plus, as Joseph told a meeting of the Metropolitan (New York) Area Geriatric Society, the animals were powered by leg muscles "that look like those in the legs of young rats."

As good as blueberries are by themselves, Joseph finds, they are more biologically extravagant in combination with certain other foods. Blueberries have a particularly complex relationship with fats - both the good kind and the bad.

Eaten, for example, with oil-rich walnuts or avocados, the berries act synergistically to keep brain cell membranes youthfully flexible - a feat of wide impact since every flicker of thought or intentional movement starts with a transaction across a brain cell membrane. Then, too, blueberries lower the body's burden of cholesterol, minimizing the threat of atherosclerosis in the blood vessels that supply heart and brain.

Walnuts, Joseph finds, contain both polyphenols, like dark berries, and omega-3 fatty acids. They are especially rich in the omega-3 fat known as alpha-linolenic acid. Nerve cell membranes, he explained to the New York conference, are host to a wide array of receptors, such as those for serotonin and other neurotransmitters; receptors are the gateway to nerve cells. But with age, the membranes become rigid and blunt the actions of receptors.

"Together, the polyphenols in berries and walnuts and the fatty acids in the walnuts fluidize the nerve cell membrane," Joseph reported. "They make it more responsive to a wide array of signals," increasing the efficiency of all transactions. The membrane effects are at least as powerful as the antioxidant effects that have already earned blueberries a place at the well-appointed table.

Walnuts may amplify the effects of richly hued berries in still other ways. The equivalent of one ounce of walnuts - the amount recommended for heart health - may help block inflammation at the cellular level, a process now implicated in cardiovascular disease, Alzheimer's disease, and other degenerative processes of aging. "All this is reversible," Joseph insists. "The effects of natural combinations such as walnuts and blueberries - or strawberries or blackberries - are powerful."

In a study led by Joseph's occasional collaborator, Canadian Wilhelmina Kalt, researchers found that a diet moderately rich in blueberries also directly affects cholesterol transport in the body. The net effect is a decrease in total cholesterol and especially of artery-clogging LDL, or low-density lipoprotein, cholesterol.

Kalt's study, published recently in the British Journal of Nutrition, is the first to document lipid-lowering effects of blueberries. The investigators called the results especially notable because they were achieved in pigs - models of human heart disease - with "doses that could reasonably be achieved in the adult human diet," about a cup of berries a day. The anthocyanins had the greatest cholesterol-lowering effect in those animals fed diets rich in other plant foods as well. Kalt, a Nova Scotia-based researcher with Agri-Food

Canada, spends part of every summer meeting with Joseph and his "brainberry group" at the halfway point, in Maine.

"We have fun in here," Joseph says of his research lab, filled with baskets of fruit. "And it's fun to talk about. It's something that people can use right now. Adding walnuts and berries or purple grape juice to the diet could delay the onset of the degenerative diseases of aging."

It's never too late

The right dietary changes have immediate brain payoffs at any age, contends Joseph. They can slow down neural aging. He advises:

- Eat plenty of colorful fruits and vegetables, which are high in antioxidants, along with nuts such as almonds, walnuts, and pecans.

- Spice up your food with circumin, which has neuroprotective effects.

- Consume foods rich in folic acid to preserve memory.

- Maintain zinc levels to help ward off Alzheimer's disease.

When Myelin Is The Cause, Might Nicotine Be the Cure?

January 2007

The development, maintenance, and repair of myelin is the single most important factor affecting cognition and behavior, according to a UCLA neurology professor who has collected extensive data on the nerve insulator. In an article to be published in an upcoming issue of Biological Psychiatry, George Bartzokis, MD, asserts that myelin may be the universal cause or contributor to a wide range of neuropsychological brain disorders, from autism to Alzheimer’s disease. Dr. Bartzokis, who directs the UCLA Memory Disorders and Alzheimer’s Disease Clinic in Los Angeles, suggests that using noninvasive imaging technology to view the miles of myelin in the brain as it grows and breaks down throughout a human life cycle may offer insights leading to the development of new treatments for brain disorders. Nicotine, which studies have suggested enhances the growth and maintenance of myelin, could be one such novel treatment.

In some of the first research to approach brain disorders from a myelin-centered point of view, Dr. Bartzokis studied the effects of cholinergic treatments, including acetylcholinesterase inhibitors (AChEIs) that are used to improve a neuron’s synaptic signaling in people with diseases such as Alzheimer’s. Some data suggest that such treatments may even modify or slow the progression of Alzheimer’s as well as other diseases.

Nicotine, Age, and Disease

Dr. Bartzokis hypothesizes that cholinergic stimulation at neuronal synapses affects the myelination process throughout brain development in the course of a human’s lifetime.He found in clinical trials that cholinergic treatment protects brain cells, while postmortem and imaging data have shown cholinergic receptor changes during brain development and degeneration. Trials have also revealed epidemiologic evidence that nicotine from tobacco may have a protective effect on degenerative diseases of old age and younger psychiatric populations. Cholinergic treatments have also shown efficacy in the aging process and age-related neurodegenerative diseases such as Alzheimer’s disease, as well as some neurodegenerative diseases like autism and ADHD.

According to Dr. Bartzokis, myelination development resembles an inverted “U” over the course of a lifetime, with increasing myelin development peaking in middle age and breaking down and declining in later years. Following the analogy of the Internet, Dr. Bartzokis says the “connectivity” provided by myelination increases speed by 10-fold and decreases refractory time by 34-fold. Thus, myelination increases the “bandwidth,” or processing capacity, of our brain’s Internet by 340-fold and is “indispensable for developing our uniquely elaborate higher cognitive functions.”

Different cortical regions myelinate at different ages, with later-myelinating oligodendrocytes growing increasingly more complex as we age. Irregular development during the most complex stages of the myelination process contributes to several of the neuropsychiatric disorders that tend to manifest in the early years. These disorders—eg, autism, ADHD, schizophrenia, mood disorders, addictions—are defined by overlapping cognitive and behavioral symptom clusters.

According to Dr. Bartzokis, healthy individuals with normal myelin development typically lose 45% of their myelinated fiber length when they reach the degeneration phase in adulthood. This change in the brain may cause progressive losses of memory and cognitive functions, as well as mild to severe behavioral changes.

The loss of myelin and its components such as sulfatide, myelin basic protein, and cholesterol begins early in the development of Alzheimer’s disease, well before diagnosis of dementia or mild cognitive impairment. The myelin breakdown process is further modified by risk factors such as the presence of APOE ε4 or environmental factors such as a head trauma.

Nicotine's Effect on Myelination and Repair

Recent research has unveiled some surprising findings on the influence of nicotine on myelination and the aging process. Direct nicotinic stimulation associated with smoking has been shown to increase nicotinic receptors in the late myelinating frontal and temporal intracortical regions. Unlike most agonists, nicotine causes an up-regulation of its receptors and has been shown to accelerate brain function recovery when white matter is damaged.

Nicotine dependence is common among people with psychiatric disorders. Some researchers have suggested the high prevalence of nicotine use among the psychiatric population represents an unconscious effort to “self-medicate.” Research on proteins has suggested that nicotine may marginally increase the expression of myelin proteins; other addictive drugs (eg, cocaine, alcohol) along with developmental diseases (eg, schizophrenia, bipolar disorder, depression) show a decrease of these proteins.

Other research has found an association between nicotinic stimulation and protective effects in schizophrenia and autism, where cortical myelination deficits have been documented. While nicotine has well-known negative effects on overall health, smoking during later years is also associated with a reduced likelihood of the development of degenerative conditions like Alzheimer’s and Parkinson’s diseases. Using the myelin-centered model, the apparent beneficial aspects of smoking on brain disorders can be attributed to nicotine’s stimulation of oligodendrocyte precursors. Dr. Bartzokis believes that nicotine, delivered through a patch, not through smoking cigarettes, should be studied for its efficacy in promoting the growth and maintenance of myelin, and that AChEIs “deserve much closer scrutiny” as a therapy for the prevention of both developmental and degenerative brain disorders.

—Kathlyn Stone

Suggested Reading
Bartzokis G. Acetylcholinesterase inhibitors may improve myelin integrity. Biol Psychiatry. 2006 Oct 26; [Epub ahead of print].
Bartzokis G, Lu PH, Mintz J. Quantifying age-related myelin breakdown with MRI: novel therapeutic targets for preventing cognitive decline and Alzheimer’s disease. J Alzheimers Dis. 2004;6(6 suppl):S53-S59.
Doody RS, Geldmacher DS, Gordon B, et al. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol. 2000;58:427-433.
Morens DM, Grandinetti A, Reed D, et al. Cigarette smoking and protection from Parkinson’s disease: false association or etiologic clue? Neurology. 1995;45:1041-1051.

http://www.neuropsychiatryreviews.com/07jan/myelin.html

Multiple Sclerosis may not be an Auto-Immune Disease

New Data Challenge Theories Of Multiple Sclerosis

Earliest Pathology Exams Uncover Unexpected Cell Death

A new view of multiple sclerosis (MS) may arise from the first extensive study of brain tissue from the earliest hours during a bout of the disease. The results, published February 23, 2004, in the online edition of the Annals of Neurology, suggest that the earliest event is not, as previously believed, a misguided immune system attack on a brain substance called myelin. The full study will be available on February 23 via Wiley InterScience(http://www.interscience.wiley.com/annalsofneurology).

Instead, the first event appears to be the death of the brain cells that produce myelin, triggering a subsequent immune system mop-up operation to clean up the cells and the myelin, said author John W. Prineas, MBBS, of the University of Sydney in Australia.

Multiple sclerosis is an enigmatic disorder of the nerve fibers of the brain and spinal cord. Scarring (sclerosis) replaces myelin, which normally insulates the nerves from damage and speeds electrical conduction through the fibers.

Depending on which nerve fibers are hindered, patients can experience problems ranging from weakness and clumsiness to numbness, visual disturbances, and even emotional and intellectual alterations. In some patients, MS manifests itself in cycles of relapse and remission; in other patients, the disease may progress to a stage of severe debilitation, either slowly or rapidly.

According to Prineas, the study he conducted with co-author Michael H. Barnett, MBBS, began several years ago while he was working at the New Jersey Medical School in Newark. A fellow neuropathologist in Manhattan asked whether Prineas and his colleagues would be interested in examining brain tissue from a 14-year-old girl who died unexpectedly 17 hours into a relapse.

Sudden death can occur in MS if the damage (or lesion) occurs in parts of the brain that control vital functions such as breathing and blood circulation.

"This patient proved to be unique in the history of multiple sclerosis in that there was lesion available for study that was less than a day old," said Prineas.

According to the dominant theory of MS, when the researchers examined the hours-old lesion, they should have found the beginnings of an immune system attack.

But Prineas and Barnett noticed that the myelin in the lesion was still intact, and there was no evidence that the typical armada of immune system cells and molecules had moved into the area yet. Instead, oligodendrocytes cells, which produce the myelin, were dying. Myelin is, in fact, an extension of oligodendrocytes that wraps itself around nearby nerve fibers.

"This encouraged us to re-examine other early MS cases in our brain bank," said Prineas. "Similar lesions, albeit extremely rare, were identified in a number of other early MS cases, which allowed us to conclude that the changes observed probably occur at the onset of any typical new lesion."

The results could have significant consequences for MS research, much of which is focused on understanding why the immune system attacks myelin. The focus may have to shift to understanding why the myelin-producing cells begin to die.

"The important point, at this stage of our investigation, seems to be that we have no laboratory model for this sort of pathology," said Prineas.

Article: "Relapsing and Remitting Multiple Sclerosis:
Pathology of the Newly Forming Lesion," by Michael H.
Barnett, MBBS and John W. Prineas, MBBBS, Annals of
Neurology online edition; February 23, 2004.

Etude clinique de phase II portant sur l'atacicept

Merck Serono annonce la mise en place d'une étude clinique de phase II portant sur l'atacicept dans le traitement des formes récurrentes de sclérose en plaques

GENEVE, Suisse, April 30 /PRNewswire/ -- Merck Serono - une division de Merck KGaA, Darmstadt, Allemagne - et son partenaire ZymoGenetics, Inc. (NASDAQ: ZGEN) ont annoncé aujourd'hui le début d'une étude clinique de phase II destinée à évaluer le profil de tolérance et l'efficacité de l'atacicept dans le traitement des formes récurrentes de sclérose en plaques.

"La mise en place de cette étude portant sur l'atacicept souligne l'engagement à long terme de Merck Serono envers les patients atteints de sclérose en plaques", a commenté Anton Hoos, Directeur du Développement Clinique de Merck Serono. "En apportant un nouveau mécanisme d'action et une administration aisée, l'atacicept dispose du potentiel pour compléter les options thérapeutiques actuellement disponibles pour le traitement de la sclérose en plaques."

"Les patients atteints de sclérose en plaques doivent pouvoir disposer de davantage d'options thérapeutiques", a déclaré Nicole Onetto, Directrice Médicale de ZymoGenetics. "Nos modèles précliniques ont mis en évidence l'activité biologique de l'atacicept dans la sclérose en plaques et, compte tenu du nombre croissant de données publiées en faveur du rôle important joué par les cellules B et les anticorps dans la physiopathologie de la sclérose en plaques, nous pensons qu'il y a un rationnel solide pour mener l'évaluation clinique de l'atacicept chez des patients atteints de formes récurrentes de la maladie."

L'étude randomisée, multicentrique, à quatre bras, en double aveugle, contrôlée par placebo, permettra d'évaluer le profil de tolérance et l'efficacité d'un traitement par l'atacicept pendant une durée de 36 semaines chez des patients atteints de formes récurrentes de sclérose en plaques. L'objectif principal de l'étude est d'évaluer l'efficacité de l'atacicept pour réduire l'inflammation du système nerveux central chez des sujets atteints de formes récurrentes de sclérose en plaques, en pratiquant une série d'examens IRM (imagerie par résonance magnétique).

Environ 300 patients atteints de cette forme de la maladie et répondant aux critères d'éligibilité de l'étude recevront après randomisation, par voie sous-cutanée, pendant 36 semaines, une des trois doses préalablement sélectionnées d'atacicept ou un placebo. Les patients seront suivis jusqu'à la 48ème semaine.

A propos de l'atacicept

Merck Serono et ZymoGenetics développent l'atacicept (antérieurement dénommé TACI-Ig) comme traitement potentiel de maladies auto-immunes telles que le lupus érythémateux disséminé, la néphropathie lupique, la polyarthrite rhumatoïde et la sclérose en plaques, ainsi que des hémopathies à cellules B.

L'atacicept contient le récepteur soluble TACI qui se lie aux cytokines BLyS et APRIL. Ces cytokines, qui appartiennent à la même famille que le facteur de nécrose tumorale (TNF), interviennent dans la survie des cellules B et la production d'auto-anticorps impliqués dans la survenue de certaines maladies auto-immunes comme le lupus érythémateux disséminé. Les données actuelles indiquent que les concentrations de BLyS et APRIL sont élevées chez les patients atteints de polyarthrite rhumatoïde, de lupus érythémateux disséminé, d'hémopathies à cellules B ou de sclérose en plaques. L'atacicept agit à différents stades du développement des cellules B et pourrait empêcher la survie des cellules responsables de la production des anticorps.

Merck Serono et la sclérose en plaques

Merck Serono est un leader dans le domaine de la sclérose en plaques (SEP) avec Rebif(R) (interféron bêta-1a), médicament modificateur de l'évolution de la maladie, indiqué dans le traitement des formes récurrentes de SEP, et enregistré dans plus de 80 pays à travers le monde. Outre Rebif(R), le portefeuille de traitements de la SEP de la société comprend également, aux Etats-Unis, un second médicament: Novantrone(R) (solution injectable concentrée de mitoxantrone), destiné au traitement des formes progressives de la maladie. Des informations détaillées relatives à la prescription de ces médicaments peuvent être obtenues en contactant la société ou sur son site internet. Merck Serono développe actuellement d'autres options thérapeutiques, notamment la forme orale de la cladribine, actuellement en essai clinique de Phase III et susceptible de devenir le premier traitement par voie orale de la SEP, ainsi que plusieurs autres produits à un stade plus précoce de développement. Merck Serono s'affirme également comme un leader en travaillant à une meilleure compréhension du rôle de la génétique dans la SEP.

A propos de la sclérose en plaques

La sclérose en plaques (SEP) est un état inflammatoire chronique du système nerveux. C'est la maladie neurologique d'origine non-traumatique la plus fréquente chez l'adulte jeune. D'après l'Organisation Mondiale de la Santé, environ 2,5 millions de personnes seraient affectées par la maladie dans le monde. Les symptômes de la SEP sont variables, les plus fréquents étant une vision trouble, une insensibilité ou des fourmillements des membres, ainsi que des troubles de la force musculaire et de la coordination. Les formes récidivantes de la SEP sont les plus fréquentes.

A propos de Merck Serono

Merck Serono est la division spécialisée dans les médicaments de prescription innovants de Merck, un groupe pharmaceutique et chimique mondial. Merck Serono, dont le siège est basé à Genève (Suisse), recherche, développe, produit et commercialise des médicaments innovants visant à aider des patients dont les besoins médicaux sont insatisfaits. Merck Serono dispose d'une expertise à la fois pour les médicaments obtenus par synthèse chimique et pour ceux issus de la biotechnologie. En Amérique du Nord (Etats-Unis et Canada), les activités de Merck Serono sont menées sous la dénomination EMD Serono.

Merck Serono met à la disposition des patients des médicaments phares dans les domaines de l'oncologie (Erbitux(R)), de la sclérose en plaques (Rebif(R)), de l'infertilité (Gonal-f(R)), des troubles endocriniens et cardio-métaboliques (Glucophage(R), Concor(R), Saizen(R), Serostim(R)), ainsi que du psoriasis (Raptiva(R)).

Avec un investissement annuel de 1 milliard d'euros en Recherche & Développement, Merck Serono a pour objectif de poursuivre la croissance de ses activités dans des domaines thérapeutiques spécialisés, dont les maladies neurodégénératives, l'oncologie, la fertilité et l'endocrinologie, ainsi que dans de nouveaux domaines thérapeutiques tels que les maladies auto-immunes et inflammatoires.

A propos de Merck

Fort d'une histoire qui a commencé en 1668 et d'un futur façonné par 31 681 employés répartis dans 60 pays, Merck est un groupe pharmaceutique et chimique mondial dont les ventes se sont élevées à 7,1 milliards d'euros en 2007. L'une des clés de sa réussite tient au sens de l'innovation et à l'esprit d'initiative de ses employés. Les activités de Merck sont chapeautées par la société Merck KGaA, dont le capital est détenu à hauteur d'environ 70% par la famille Merck et à hauteur d'environ 30% par des actionnaires extérieurs. L'ancienne filiale américaine Merck & Co. est totalement autonome depuis sa séparation en 1917, et n'a depuis plus aucun lien avec le groupe Merck Serono.

Pour plus d'informations, vous pouvez consulter les sites http://www.merckserono.net ou http://www.merck.de

Distributed by PR Newswire on behalf of Merck Serono International SA

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Des chercheurs constatent qu’un anticorps stimule la réparation de la myéline

Communication médicale
Le 6 novembre 2007
Résumé

Des chercheurs subventionnés par la National Multiple Sclerosis Society (organisme américain de la sclérose en plaques) rapportent qu’un anticorps peut stimuler la réparation de la myéline chez les souris atteintes d’une maladie semblable à la sclérose en plaques (SP). La myéline est la gaine isolante des fibres nerveuses. Cette substance est attaquée et détériorée au cours du processus pathologique de la SP. Les chercheurs ont également souligné que l’anticorps en question, le rHIgM22, demeure efficace chez la souris lorsqu’il est combiné à la méthylprednisolone, corticostéroïde employé dans le traitement des poussées chez les personnes atteintes de SP. Le Dr Moses Rodriguez et Art Warrington, Ph.D. (Mayo Clinic and Foundation, Rochester, MN) ont fait état de leurs observations au congrès annuel de l’association américaine de neurologie, tenu à Washington, DC, cette semaine (résumé no T-109).
Détails

Bien que l’organisme puisse réparer une partie des lésions causées à la myéline par la sclérose en plaques (SP), les résultats sont insuffisants. C’est pourquoi on étudie actuellement la possibilité de stimuler les mécanismes internes de réparation au moyen de protéines du système immunitaire appelées anticorps. Le Dr Rodriguez et ses collaborateurs ont identifié des anticorps humains qui ciblent les cellules productrices de myéline (oligodendrocytes) dans le cerveau et la moelle épinière et s’y fixent. Ils ont également trouvé un moyen de produire ces anticorps en laboratoire. Grâce à une subvention de recherche de la National MS Society, comprenant une bourse du Collaborative MS Research Center, le Dr Rodriguez a réuni une équipe de chercheurs dans le but d’explorer plus à fond cette possibilité thérapeutique.

L’équipe Mayo a éprouvé sa stratégie de réparation sur un modèle murin (souris) présentant une maladie chronique et progressive, semblable à la SP. Les souris ont reçu une dose unique de quantités variables de l’anticorps. Le processus de réparation de la myéline a été enclenché par une faible quantité (23 µg) de l’anticorps, et l’état des souris s’est stabilisé après cinq semaines. Lorsque l’anticorps a été associé à des doses quotidiennes de méthylprednisolone, médicament utilisé pour traiter les poussées chez les personnes atteintes de SP, il a continué de promouvoir les mécanismes de réparation, et l’état des souris ne s’est pas aggravé.

Bien que ces observations demandent à être confirmées par d’autres études sur les animaux et les humains, elles nous permettent de faire un pas de plus dans la recherche de moyens de stimuler la réparation de la myéline chez les personnes atteintes de SP.

Adaptation d’un communiqué de la National MS Society.