Posts tagged brain

ScienceDaily (Apr. 24, 2012) — Toxic prions in the brain can be detected with self-illuminating polymers. The originators, at Linköping University in Sweden, has now shown that the same molecules can also render the prions harmless, and potentially cure fatal nerve-destroying illnesses.

Linköping researchers and their colleagues at the University Hospital in Zürich tested the luminescent conjugated polymers, or LCPs, on tissue sections from the brains of mice that had been infected with prions. The results show that the number of prions, as well as their toxicity and infectibility, decreased drastically. This is the first time anyone has been able to demonstrate the possibility of treating illnesses such as mad cow disease and Creutzfeldt-Jacobs with LCP molecules.

"When we see this effect on prion infections, we believe the same approach could work on Alzheimer’s disease as well," says Peter Nilsson, researcher in Bioorganic Chemistry funded by ERC, the European Research Council.

Along with professors Per Hammarström and Adriano Aguzzi and others, he is now publishing the results in The Journal of Biological Chemistry.

Prions are diseased forms of normally occurring proteins in the brain. When they clump together in large aggregates, nerve cells in the surrounding area are affected, which leads to serious brain damage and a quick death. Prion illnesses can be inherited, occur spontaneously or through infection, for example through infected meat — as was the case with mad cow disease.

The course of the illness is relentless when the prions fall to pieces and replicate at an exponential rate. When researchers inserted the LCP molecules into their model system, the replication was arrested, possible through stabilizing the prion aggregates.

The variable components in an LCP are various chemical subgroups attached onto the polymer. In the published study, eight different substances were tested, and all of them had significant effect on the toxicity of the prions.

"Based on these results, we can now customise entirely new molecules with potentially even better effect. These are now being tested on animal models," Nilsson says.

Researchers want to go even further and test whether the molecules will function on fruit flies with an Alzheimer’s-like nerve disorder. Alzheimer’s is caused by what is known as amyloid plaque, which has a similar but slower course than prion diseases.

Source: Science Daily

April 23rd, 2012

A team of scientists from Johns Hopkins and elsewhere have developed nano-devices that successfully cross the brain-blood barrier and deliver a drug that tames brain-damaging inflammation in rabbits with cerebral palsy.

Schematic picture of a dendrimer with multiple branches that are tagged with drug molecules and imaging agents. Image adapted from press release image from Johns Hopkins.

A report on the experiments, conducted at Wayne State University in collaboration with the Perinatology Research Branch of the National Institute of Child Health and Human Development, before the lead and senior investigators moved to Johns Hopkins, is published in the April 18 issue of Science Translational Medicine.

For the study, researchers used tiny, manmade molecules laced with N-acetyl-L-cysteine (NAC), an anti-inflammatory drug used as antidote in acetaminophen poisoning. The researchers precision-targeted brain cells gone awry to halt brain injury. In doing so they improved the animals’ neurologic function and motor skills.

The new approach holds therapeutic potential for a wide variety of neurologic disorders in humans that stem from neuro-inflammation, including Alzheimer’s disease, stroke, autism and multiple sclerosis, the investigators say.

The scientists caution that the findings are a long way from human application, but that the simplicity and versatility of the drug-delivery system make it an ideal candidate for translation into clinical use.

“In crossing the blood-brain barrier and targeting the cells responsible for inflammation and brain injury, we believe we may have opened the door to new therapies for a wide-variety of neurologic disorders that stem from an inflammatory response gone haywire,” says lead investigator Sujatha Kannan, M.D., now a pediatric critical-care specialist at Johns Hopkins Children’s Center.

Cerebral palsy (CP), estimated to occur in three out of 1,000 newborns, is a lifelong, often devastating disorder caused by infection or reduced oxygen to the brain before, during or immediately after birth. Current therapies focus on assuaging symptoms and improving quality of life, but can neither reduce nor reverse neurologic damage and loss of motor function.

Neuro-inflammatory damage occurs when two types of brain cells called microglia and astrocytes — normally deployed to protect the brain during infection and inflammation — actually damage it by going into overdrive and destroying healthy brain cells along with damaged ones.

Directly treating cells in the brain has long proven difficult because of the biological and physiological systems that have evolved to protect the brain from blood-borne infections. The quest to deliver the drug to the brain also involved developing a technique to get past the brain-blood barrier, spare healthy brain cells and deliver the anti-inflammatory drug exclusively inside the rogue cells.

To do all this, the scientists used a globular, tree-like synthetic molecule, known as a dendrimer. Its size — 2,000 times smaller than a red blood cell — renders it fit for travel across the blood-brain barrier. Moreover, the dendrimer’s tree-like structure allowed scientists to attach to it molecules of an anti-inflammatory NAC. The researchers tagged the drug-laced dendrimers with fluorescent tracers to monitor their journey to the brain and injected them into rabbits with cerebral palsy six hours after birth. Another group of newborn rabbits received an injection of NAC only.

Not only did the drug-loaded dendrimers make their way inside the brain but, once there, were rapidly swallowed by the overactive astrocytes and microglia.

“These rampant inflammatory cells, in effect, gobbled up their own poison,” Kannan says.

“The dendrimers not only successfully crossed the blood-brain barrier but, perhaps more importantly, zeroed in on the very cells responsible for neuro-inflammation, releasing the therapeutic drug directly into them,” says senior investigator Rangaramanujam Kannan, Ph.D., of the Center for Nanomedicine at the Johns Hopkins Wilmer Eye Institute.

Animals treated with dendrimer-borne NAC showed marked improvement in motor control and coordination within five days after birth, nearly reaching the motor skill of healthy rabbits. By comparison, rabbits treated with dendrimer-free NAC showed minimal, if any, improvement, even at doses 10 times higher than the dendrimer-borne version. Animals treated with the dendrimer-delivered drug also showed better muscle tone and less stiffness in the hind leg muscles, both hallmarks of CP.

Brain tissue analysis revealed that rabbits treated with dendrimer-borne NAC had notably fewer “bad” microglia — the inflammatory cells responsible for brain damage — as well as markedly lower levels of other inflammation markers. They also had better preserved myelin, the protein that sheaths nerves and is stripped or damaged in CP and other neurologic disorders. And even though CP is marked by neuron death in certain brain centers, animals who received dendrimer-borne NAC had higher number of neurons in the brain regions responsible for coordination and motor control, compared with untreated animals and those treated with NAC only.

The findings suggest that the treatment not only reduces inflammation in the cells, but may also prevent cell damage and cell death, the researchers said. The Kannans, who are married, say they plan to follow some treated animals into adulthood to ensure the improvements are not temporary.

Source: Neuroscience News

April 23, 2012

St. Jude Children’s Research Hospital scientists have rewritten the job description of the protein TopBP1 after demonstrating that it guards early brain cells from DNA damage. Such damage might foreshadow later problems, including cancer.

Researchers showed that cells in the developing brain require TopBP1 to prevent DNA strands from breaking as the molecule is copied prior to cell division. Investigators also reported that stem cells and immature cells known as progenitor cells involved at the beginning of brain development are more sensitive to unrepaired DNA damage than progenitor cells later in the process. Although more developmentally advanced than stem cells, progenitor cells retain the ability to become one of a variety of more specialized neurons.

"Such DNA strand breaks have great potential for creating mutations that push a normal cell toward malignancy," said Peter McKinnon, Ph.D., a St. Jude Department of Genetics member and the paper’s senior author. "When we selectively knocked out TopBP1 in mice, the amount of DNA damage we saw suggests that TopBP1 is likely to be a tumor suppressor. We are exploring that question now."

The work appeared in the April 22 online edition of the scientific journal Nature Neuroscience. The research builds on McKinnon’s interest in DNA repair systems, including the enzymes ATM and ATR, which are associated with a devastating cancer-prone neurodegenerative disease in children called ataxia telangiectasia, and a neurodevelopmental disorder called Seckel syndrome.

TopBP1 was known to activate ATR. Previous laboratory research by other investigators also suggested that activation made TopBP1 indispensable for DNA replication and cell proliferation. This study, however, showed that was not the case. Most progenitor cells in the embryonic mouse brain kept dividing after investigators switched off the TopBP1 gene. 

Read more …

April 23, 2012

A cellular protein called HDAC6, newly characterized as a gatekeeper of steroid biology in the brain, may provide a novel target for treating and preventing stress-linked disorders, such as depression and post-traumatic stress disorder (PTSD), according to research from the Perelman School of Medicine at the University of Pennsylvania.

Glucocorticoids are natural steroids secreted by the body during stress. A small amount of these hormones helps with normal brain function, but their excess is a precipitating factor for stress-related disorders.

Glucocorticoids exert their effects on mood by acting on receptors in the nucleus of emotion–regulating neurons, such as those producing the neurotransmitter serotonin. For years, researchers have searched for ways to prevent deleterious effects of stress by blocking glucocorticoids in neurons. However, this has proved difficult to do without simultaneously interfering with other functions of these hormones, such as the regulation of immune function and energy metabolism.

In a recent Journal of Neuroscience paper, the lab of Olivier Berton, PhD, assistant professor of Psychiatry, shows how a regulator of glucocorticoid receptors may provide a path towards resilience to stress by modulating glucocorticoid signaling in the brain. The protein HDAC6, which is particularly enriched in serotonin pathways, as well as in other mood-regulatory regions in both mice and humans, is ideally distributed in the brain to mediate the effect of glucocorticoids on mood and emotions. HDAC6 likely does this by controlling the interactions between glucocorticoid receptors and hormones in these serotonin circuits.

Experiments that first alerted Berton and colleagues to a peculiar role of HDAC6 in stress adaptation came from an approach that reproduces certain clinical features of traumatic stress and depression in mice. The animals are exposed to brief bouts of aggression from trained “bully” mice. In most aggression-exposed mice this experience leads to the development of a lasting form of social aversion that can be treated by chronic administration of antidepressants. 

Read more …

April 23, 2012

Ten years ago, a landmark clinical trial in Canada demonstrated the unequivocal effectiveness of brain surgeries for treating uncontrolled epilepsy, but since then the procedure has not been widely adopted—in fact, it is dramatically underutilized according to a new study from the University of California, San Francisco (UCSF).

The study, published this month in the journal Neurology, showed that the number of Americans having the surgery has not changed in the decade since release of the effectiveness study, though surgical treatment is now uniformly encouraged by neurology and neurosurgery professional societies.

The U.S. Centers for Disease Control and Prevention estimates that 2 million Americans have epilepsy. Hundreds of thousands of these men, women and children suffer from uncontrolled seizures, but nationally only a few hundred are treated surgically each year with UCSF performing about 50 of the operations.

Among people who do have the operation, the study found, there are significant disparities by race and insurance status. White patients were more likely to have surgery than racial minorities, and privately insured patients were more likely to undergo surgery than those with Medicaid or Medicare.

"As a medical community, we are not practicing evidence-based medicine with regard to the treatment of patients who have epilepsy," said Edward Chang, MD, chief of adult epilepsy surgery in the UCSF Department of Neurological Surgery and the UCSF Epilepsy Center. "There are a lot of people who are taking medications and continuing to have seizures even though they can potentially be seizure-free."

A MODERN SURGERY FOR AN ANCIENT DISEASE

Epilepsy has been recognized as an important neurological condition since ancient times and its name means “seizures” in Greek. It can be inherited or it can be caused by anything that injures or irritates the brain. Hippocrates, the father of western medicine, described it in detail in his writings some 2,500 years ago, and it is believed to have afflicted many famous people throughout history, including Julius Caesar.

UCSF is one of the world’s leading institutions involved in epilepsy research, with one of the few medical centers that has top-ranking departments in relevant areas: neurology, biomedical imaging, and neurosurgery.

Paul Garcia, MD, director of the clinical epilepsy program and a study co-author, said that most patients referred to UCSF for surgical evaluation have had uncontrolled seizures for many years despite trying several medications. Research has shown that after the first two medicines fail, it is uncommon for patients to gain complete seizure control with medical treatment alone. Without control over their seizures, patients are at risk for physical injuries or even dying. Furthermore, the seizures often interfere with normal life activities such as driving, studying and working.

Read more …

April 23, 2012

Omega-3 fatty acid supplements were not associated with beneficial effects on disease activity in patients with relapsing-remitting multiple sclerosis, according to a report of a randomized controlled trial published Online First by Archives of Neurology.

Multiple sclerosis is a chronic, incurable disease of the central nervous system that affects about 2.5 million people worldwide. Some patients use, or have tried, omega-3 fatty acids supplementation to control the disease because the essential fatty acids could theoretically have anti-inflammatory and neuroprotective effects in multiple sclerosis, the authors write in their study background.

Øivind Torkildsen, M.D., Ph.D., of Haukeland University Hospital, Bergen, Norway, and colleagues included 92 patients with multiple sclerosis in their double-blind, placebo-controlled trial to examine whether omega-3 fatty acid supplementation as a monotherapy (single therapy) or in combination with subcutaneous (under the skin) interferon beta-1a could reduce disease activity.

Half of the patients (46) were given omega-3 fatty acids – 1350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid daily - and the other half (46) were administered placebo. After six months, all patients received interferon beta-1a three times a week for another 18 months. Researchers used magnetic resonance imaging (MRI) to measure disease activity by the number of new T1-weighted gadolinium-enhancing lesions in the brain.

"The results from this study did not show any beneficial effects of ω-3 [omega-3] fatty acid supplementation on disease activity in multiple sclerosis as a monotherapy or in combination with interferon beta," the authors comment. They note their results were in contrast with two other studies reporting a possible positive effect.

The median number of new T1-weighted gadolinium-enhancing lesions was three in the omega-3 fatty acids group and two in the placebo group during the first six months, according to the study results. The results indicate no difference between the two groups in the number of relapses during the first six months of treatment or after 24 months. No differences were detected either in fatigue or quality-of-life scores.

However, the authors comment their data do not suggest that omega-3 fatty acid supplementation was harmful or that it interfered with interferon beta treatment, which they note can reduce disease activity in the relapsing-remitting course of the disease.

"The design of this study allowed us to compare the effect of ω-3 fatty acid supplementation both against placebo alone and in combination with interferon beta. As expected, the MRI disease activity was significantly reduced when interferon beta-1a was introduced," they conclude.

Provided by JAMA and Archives Journals

Source: medicalxpress.com

April 23, 2012

According to a new study, the neuron-killing pathology of Alzheimer’s disease (AD), which begins before clinical symptoms appear, requires the presence of both amyloid-beta (a-beta) plaque deposits and elevated levels of an altered protein called p-tau.

Without both, progressive clinical decline associated with AD in cognitively healthy older individuals is “not significantly different from zero,” reports a team of scientists at the University of California, San Diego School of Medicine in the April 23 online issue of the Archives of Neurology.

"I think this is the biggest contribution of our work," said Rahul S. Desikan, MD, PhD, research fellow and resident radiologist in the UC San Diego Department of Radiology and first author of the study. "A number of planned clinical trials – and the majority of Alzheimer’s studies – focus predominantly on a-beta. Our results highlight the importance of also looking at p-tau, particularly in trials investigating therapies to remove a-beta. Older, non-demented individuals who have elevated a-beta levels, but normal p-tau levels, may not progress to Alzheimer’s, while older individuals with elevated levels of both will likely develop the disease."

The findings also underscore the importance of p-tau as a target for new approaches to treating patients with conditions ranging from mild cognitive impairment (MCI) to full-blown AD. An estimated 5.4 million Americans have AD. It’s believed that 10 to 20 percent of Americans age 65 and older have MCI, a risk factor for AD. Some current therapies appear to delay clinical AD onset, but the disease remains irreversible and incurable.

"It may be that a-beta initiates the Alzheimer’s cascade," said Desikan. "But once started, the neurodegenerative mechanism may become independent of a-beta, with p-tau and other proteins playing a bigger role in the downstream degenerative cascade. If that’s the case, prevention with anti-a-beta compounds may prove efficacious against AD for older, non-demented individuals who have not yet developed tau pathology. But novel, tau-targeting therapies may help the millions of individuals who already suffer from mild cognitive impairment or Alzheimer’s disease." 

Read more …

April 23, 2012

Research shows that many treatments can help prevent migraine in certain people, yet few people with migraine who are candidates for these preventive treatments actually use them, according to new guidelines issued by the American Academy of Neurology. The guidelines, which were co-developed with the American Headache Society, will be announced at the American Academy of Neurology’s 64th Annual Meeting in New Orleans and published in the April 24, 2012, print issue of Neurology®, the medical journal of the American Academy of Neurology.

"Studies show that migraine is underrecognized and undertreated," said guideline author Stephen D. Silberstein, MD, FACP, FAHS, of Jefferson Headache Center at Thomas Jefferson University in Philadelphia and a Fellow of the American Academy of Neurology. "About 38 percent of people who suffer from migraine could benefit from preventive treatments, but only less than a third of these people currently use them."

Unlike acute treatments, which are used to relieve the pain and associated symptoms of a migraine attack when it occurs, preventive treatments usually are taken every day to prevent attacks from occurring as often and to lessen their severity and duration when they do occur.

"Some studies show that migraine attacks can be reduced by more than half with preventive treatments," Silberstein said.

The guidelines, which reviewed all available evidence on migraine prevention, found that among prescription drugs, the seizure drugs divalproex sodium, sodium valproate and topiramate, along with the beta-blockers metoprolol, propranolol and timolol, are effective for migraine prevention and should be offered to people with migraine to reduce the frequency and severity of attacks. The seizure drug lamotrigine was found to be ineffective in preventing migraine.

The guidelines also reviewed over-the-counter treatments and complementary treatments. The guideline found that the herbal preparation Petasites, also known as butterbur, is effective in preventing migraine. Other treatments that were found to be probably effective are the nonsteroidal anti-inflammatory drugs fenoprofen, ibuprofen, ketoprofen, naproxen and naproxen sodium, subcutaneous histamine and complementary treatments magnesium, MIG-99 (feverfew) and riboflavin.

Silberstein noted that while people do not need a prescription from a physician for these over-the-counter and complementary treatments, they should still see their doctor regularly for follow-up. “Migraines can get better or worse over time, and people should discuss these changes in the pattern of attacks with their doctors and see whether they need to adjust their dose or even stop their medication or switch to a different medication,” said Silberstein. “In addition, people need to keep in mind that all drugs, including over-the-counter drugs and complementary treatments, can have side effects or interact with other medications, which should be monitored.”

Provided by American Academy of Neurology
Source: medicalxpress.com 

April 22, 2012

A key protein, which may be activated to protect nerve cells from damage during heart failure or epileptic seizure, has been found to regulate the transfer of information between nerve cells in the brain. The discovery, made by neuroscientists at the University of Bristol and published in Nature Neuroscience and PNAS, could lead to novel new therapies for stroke and epilepsy.

The research team, led by Professor Jeremy Henley and Dr Jack Mellor from Bristol’s Medical School, has identified a protein, known as SUMO, responsible for controlling the chemical processes which reduce or enhance protection mechanisms for nerve cells in the brain.

These key SUMO proteins produce subtle responses to the brain’s activity levels to regulate the amount of information transmitted by kainate receptors - responsible for communication between nerve cells and whose activation can lead to epileptic seizures and nerve cell death.

Protein function is controlled by altering their structure in processes that can be independent or inter-related including phosphorylation, ubiquitination and SUMOylation. In the present work it is shown that phosphorylation of kainate receptors on its own promotes their activity. However, phosphorylation also facilitates SUMOylation of kainate receptors that reduces their activity. Thus there is a dynamic and delicate interplay between phosphorylation and SUMOylation that regulates kainate receptor function.

This fine balance between phosphorylation and SUMOylation is dependent on brain activity levels where damaging activity that occurs during stroke or epilepsy will enhance SUMOylation and therefore reduce kainate receptor function to protect nerve cells.

Dr Mellor, Senior Lecturer from the University’s School of Physiology and Pharmacology, said: “Kainate receptors are a somewhat mysterious but clearly very important group of proteins that are known to be involved in a number of diseases including epilepsy. However, we currently know little about what makes kainate receptors so important. Likewise, we also know that SUMO proteins play an important role in neuroprotection. These findings provide a link between SUMO and kainate receptors that increases our understanding of the processes that nerve cells use to protect themselves from excessive and abnormal activity.”

Professor Henley added: “This work is important because it gives a new perspective and a deeper understanding of how the flow of information between cells in the brain is regulated. The team has found that by increasing the amount of SUMO attached to kainate receptors – which would reduce communication between the cells – could be a way to treat epilepsy by preventing over-excitation of the brain’s nerve cells.”

The research follows on from previous findings published in Nature(447, 321-325) that discovered SUMO proteins target the brain’s kainate receptors altering their cellular location.

Provided by University of Bristol

Source: medicalxpress.com

April 22, 2012

New research from Mount Sinai Medical Center in New York reveals that repeated exposure to cocaine decreases the activity of a protein necessary for normal functioning of the brain’s reward system, thus enhancing the reward for cocaine use, which leads to addiction. Investigators were also able to block the ability of repeated cocaine exposure, to induce addiction. The findings, published online April 22 in the journal Nature Neuroscience, provide the first evidence of how cocaine changes the shape and size of neuron rewards in a mouse model.

Repeated exposure to cocaine decreases the expression of a protein necessary for normal functioning of the brain’s reward system, thus enhancing the reward for cocaine use and stimulating addiction. Using the protein’s light-activated form in real time, in a technique known as optogenetics, investigators were also able to block repeated cocaine exposure from enhancing the brain’s reward center from cocaine. Even though the results are very early and many steps will be important in moving from mice to humans, the researchers say that the finding opens the door to a new direction for treatment for cocaine addiction.

"There are virtually no medication regimens for cocaine addiction, only psychotherapy, and some early work with vaccines," said the study’s senior investigator, Eric Nestler, MD, PhD, Nash Family Professor of Neuroscience, Chairman of the Neuroscience and Director of the Friedman Brain Institute at Mount Sinai School of Medicine. The protein, Rac1, is found in many cells in mice, rats, monkeys, and humans, and it is known to be involved in controlling the growth of nerve cells.

Investigators “knocked out,” or deleted, the gene responsible for Rac1 production, or injected a virus to enhance expression of Rac1.

"The research gives us new information on how cocaine affects the brain’s reward center and how it could potentially be repaired," said Dr. Nestler. "This is the first case in the brain in vivo where it’s been possible to control the activity of a protein, inside nerve cells in real time. Our findings reveal new pathways and target — a proof of principle study really — for treatment of cocaine addiction."

Provided by The Mount Sinai Hospital / Mount Sinai School of Medicine

Source: medicalxpress.com