Posts tagged neurobiology
Articles and news from the latest research reports.
Scientists decode mechanisms of cell orientation in the brain
Transmembrane protein NG2 controls orientation of cell migration toward the wound / Publication in the prestigious Journal of Neuroscience
When the central nervous system is injured, oligodendrocyte precursor cells (OPC) migrate to the lesion and synthesize new myelin sheaths on demyelinated axons. Scientists at the Institute of Molecular Cell Biology at Johannes Gutenberg University Mainz (JGU) have now discovered that a distinct protein regulates the direction and movement of OPC toward the wound. The transmembrane protein NG2, which is expressed at the surface of OPCs and down-regulated as they mature to myelinating oligodendrocytes, plays an important role in the reaction of OPC to wounding. The results of this study have recently been published in the renowned Journal of Neuroscience.
The myelin sheath functions to electrically isolate axons of many nerve fibers and is synthesized by oligodendrocytes which mature from the OPC. In the case of injury, neural cells send out signaling molecules which attract the OPC. The NG2 protein helps OPCs to react to some of these and move in a directed and orientated fashion. “We were able to prove in cell biological experiments that NG2 orientates OPC toward the lesion and ensures targeted OPC migration toward the wound through the regulation of cell polarity”, explained Dr. Fabien Binamé, lead author of the study. Supported by funding of the German Research Foundation (DFG), Dr. Fabien Binamé is currently carrying out his research at the Institute of Molecular Cell Biology headed by Professor Jacqueline Trotter.
"The function and mode of operation of NG2 is not yet fully understood", added co-author Dominik Sakry, who was also involved in the study. "But it looks as if the NG2-associated regulatory mechanism becomes apparent only in cases of injury of the nervous system."
Diseases such as Multiple Sclerosis or brain tumors go hand in hand with damage of nerve tissue. “The results of our study on NG2-mediated basic mechanisms of cell orientation and migration could aid in understanding the repair of damaged demyelinated tissue, or be important for treatment of highly active migratory brain tumors which often express high levels of NG2”, said Professor Jacqueline Trotter, head of the JGU Institute of Molecular Cell Biology.
Migraine is Associated with Variations in Structure of Brain Arteries
The network of arteries supplying blood flow to the brain is more likely to be incomplete in people who suffer migraine, a new study by researchers in the Perelman School of Medicine at the University of Pennsylvania reports. Variations in arterial anatomy lead to asymmetries in cerebral blood flow that might contribute to the process triggering migraines.
The arterial supply of blood to the brain is protected by a series of connections between the major arteries, termed the “circle of Willis” after the English physician who first described it in the 17th century. People with migraine, particularly migraine with aura, are more likely to be missing components of the circle of Willis.
Migraine affects an estimated 28 million Americans, causing significant disability. Experts once believed that migraine was caused by dilation of blood vessels in the head, while more recently it has been attributed to abnormal neuronal signals. In this study, appearing in PLOS ONE, researchers suggest that blood vessels play a different role than previously suspected: structural alterations of the blood supply to the brain may increase susceptibility to changes in cerebral blood flow, contributing to the abnormal neuronal activity that starts migraine.
"People with migraine actually have differences in the structure of their blood vessels - this is something you are born with," said the study’s lead author, Brett Cucchiara, MD, Associate Professor of Neurology. "These differences seem to be associated with changes in blood flow in the brain, and it’s possible that these changes may trigger migraine, which may explain why some people, for instance, notice that dehydration triggers their headaches."
In a study of 170 people from three groups - a control group with no headaches, those who had migraine with aura, and those who had migraine without aura - the team found that an incomplete circle of Willis was more common in people with migraine with aura (73 percent) and migraine without aura (67 percent), compared to a headache-free control group (51 percent). The team used magnetic resonance angiography to examine blood vessel structure and a noninvasive magnetic resonance imaging method pioneered at the University of Pennsylvania, called Arterial spin labeling (ASL), to measure changes in cerebral blood flow.
"Abnormalities in both the circle of Willis and blood flow were most prominent in the back of the brain, where the visual cortex is located. This may help explain why the most common migraine auras consist of visual symptoms such as seeing distortions, spots, or wavy lines,” said the study’s senior author, John Detre, MD, Professor of Neurology and Radiology.
Both migraine and incomplete circle of Willis are common, and the observed association is likely one of many factors that contribute to migraine in any individual. The researchers suggest that at some point diagnostic tests of circle of Willis integrity and function could help pinpoint this contributing factor in an individual patient. Treatment strategies might then be personalized and tested in specific subgroups.
No Link Between Mercury Exposure and Autism-like Behaviors
The potential impact of exposure to low levels of mercury on the developing brain – specifically by women consuming fish during pregnancy – has long been the source of concern and some have argued that the chemical may be responsible for behavioral disorders such as autism. However, a new study that draws upon more than 30 years of research in the Republic of Seychelles reports that there is no association between pre-natal mercury exposure and autism-like behaviors.
“This study shows no evidence of a correlation between low level mercury exposure and autism spectrum-like behaviors among children whose mothers ate, on average, up to 12 meals of fish each week during pregnancy,” said Edwin van Wijngaarden, Ph.D., an associate professor in the University of Rochester Medical Center’s (URMC) Department of Public Health Sciences and lead author of the study which appears online today in the journal Epidemiology. “These findings contribute to the growing body of literature that suggest that exposure to the chemical does not play an important role in the onset of these behaviors.”
The debate over fish consumption has long created a dilemma for expecting mothers and physicians. Fish are high in beneficial nutrients such as, selenium, vitamin E, lean protein, and omega-3 fatty acids; the latter are essential to brain development. At the same time, exposure to high levels of mercury has been shown to lead to developmental problems, leading to the claim that mothers are exposing their unborn children to serious neurological impairment by eating fish during pregnancy. Despite the fact that the developmental consequences of low level exposure remain unknown, some organizations, including the U.S. Food and Drug Administration, have recommended that pregnant women limit their consumption of fish.
The presence of mercury in the environment is widespread and originates from both natural sources such as volcanoes and as a byproduct of coal-fired plants that emit the chemical. Much of this mercury ends up being deposited in the world’s oceans where it makes its way into the food chain and eventually into fish. While the levels of mercury found in individual fish are generally low, concerns have been raised about the cumulative effects of a frequent diet of fish.
The Republic of Seychelles has proven to be the ideal location to examine the potential health impact of persistent low level mercury exposure. With a population of 87,000 people spread across an archipelago of islands in the Indian Ocean, fishing is a both an important industry and a primary source of nutrition – the nation’s residents consume fish at a rate 10 times greater than the populations of the U.S. and Europe.
The Seychelles Child Development Study – a partnership between URMC, the Seychelles Ministries of Health and Education, and the University of Ulster in Ireland – was created in the mid-1980s to specifically study the impact of fish consumption and mercury exposure on childhood development. The program is one of the largest ongoing epidemiologic studies of its kind.
“The Seychelles study was designed to follow a population over a very long period of time and focus on relevant mercury exposure,” said Philip Davidson, Ph.D., principal investigator of the Seychelles Child Development Study and professor emeritus in Pediatrics at URMC. “While the amount of fish consumed in the Seychelles is significantly higher than other countries in the industrialized world, it is still considered low level exposure.”
The autism study involved 1,784 children, adolescents, and young adults and their mothers. The researchers were first able to determine the level of prenatal mercury exposure by analyzing hair samples that had been collected from the mothers around the time of birth, a test which can approximate mercury levels found in the rest of the body including the growing fetus.
The researchers then used two questionnaires to determine whether or not the study participants were exhibiting autism spectrum-like behaviors. The Social Communication Questionnaire was completed by the children’s parents and the Social Responsiveness Scale was completed by their teachers. These tests – which include questions on language skills, social communication, and repetitive behaviors – do not provide a definitive diagnosis, but they are widely used in the U.S. as an initial screening tool and may suggest the need for additional evaluation.
The mercury levels of the mothers were then matched with the test scores of their children and the researchers found that there was no correlation between prenatal exposure and evidence of autism-spectrum-like behaviors. This is similar to the result of previous studies of the nation’s children which have measured language skills and intelligence, amongst other outcomes, and have not observed any adverse developmental effects.
The study lends further evidence to an emerging belief that the “good” may outweigh the possible “bad” when it comes to fish consumption during pregnancy. Specifically, if mercury does adversely influence child development at these levels of exposure then the benefits of the nutrients found in the fish may counteract or perhaps even supersede the potential negative effects of the mercury.
“This study shows no consistent association in children with mothers with mercury levels that were six to ten times higher than those found in the U.S. and Europe,” said Davidson. “This is a sentinel population and if it does not exist here than it probably does not exist.”
“NIEHS has been a major supporter of research looking into the human health risks associated with mercury exposure,” said Cindy Lawler, Ph.D., acting branch chief at the National Institute of Environmental Health Sciences, part of National Institutes of Health. “The studies conducted in the Seychelles Islands have provided a unique opportunity to better understand the relationship between environmental factors, such as mercury, and the role they may play in the development of diseases like autism. Although more research is needed, this study does present some good news for parents.”
Breastfeeding Could Prevent ADHD
TAU research finds that breastfed children are less likely to develop ADHD later in life
We know that breastfeeding has a positive impact on child development and health — including protection against illness. Now researchers from Tel Aviv University have shown that breastfeeding could also help protect against Attention Deficit/Hyperactivity Disorder (ADHD), the most commonly diagnosed neurobehavioral disorder in children and adolescents.
Seeking to determine if the development of ADHD was associated with lower rates of breastfeeding, Dr. Aviva Mimouni-Bloch, of Tel Aviv University’s Sackler Faculty of Medicine and Head of the Child Neurodevelopmental Center in Loewenstein Hospital, and her fellow researchers completed a retrospective study on the breastfeeding habits of parents of three groups of children: a group that had been diagnosed with ADHD; siblings of those diagnosed with ADHD; and a control group of children without ADHD and lacking any genetic ties to the disorder.
The researchers found a clear link between rates of breastfeeding and the likelihood of developing ADHD, even when typical risk factors were taken into consideration. Children who were bottle-fed at three months of age were found to be three times more likely to have ADHD than those who were breastfed during the same period. These results have been published in Breastfeeding Medicine.
Understanding genetics and environment
In their study, the researchers compared breastfeeding histories of children from six to 12 years of age at Schneider’s Children Medical Center in Israel. The ADHD group was comprised of children that had been diagnosed at the hospital, the second group included the siblings of the ADHD patients, and the control group included children without neurobehavioral issues who had been treated at the clinics for unrelated complaints.
In addition to describing their breastfeeding habits during the first year of their child’s life, parents answered a detailed questionnaire on medical and demographic data that might also have an impact on the development of ADHD, including marital status and education of the parents, problems during pregnancy such as hypertension or diabetes, birth weight of the child, and genetic links to ADHD.
Taking all risk factors into account, researchers found that children with ADHD were far less likely to be breastfed in their first year of life than the children in the other groups. At three months, only 43 percent of children in the ADHD group were breastfed compared to 69 percent of the sibling group and 73 percent of the control group. At six months, 29 percent of the ADHD group was breastfed, compared to 50 percent of the sibling group and 57 percent of the control group.
One of the unique elements of the study was the inclusion of the sibling group, says Dr. Mimouni-Bloch. Although a mother will often make the same breastfeeding choices for all her children, this is not always the case. Some children’s temperaments might be more difficult than their siblings’, making it hard for the mother to breastfeed, she suggests.
Added protection
While researchers do not yet know why breastfeeding has an impact on the future development of ADHD — it could be due to the breast milk itself, or the special bond formed between mother and baby during breastfeeding, for example — they believe this research shows that breastfeeding can have a protective effect against the development of the disorder, and can be counted as an additional biological advantage for breastfeeding.
Dr. Mimouni-Bloch hopes to conduct a further study on breastfeeding and ADHD, examining children who are at high risk for ADHD from birth and following up in six-month intervals until six years of age, to obtain more data on the phenomenon.
(Source: aftau.org)
MS study targets damage affecting nerves
Multiple sclerosis treatments that repair damage to the brain could be developed thanks to new research.
A study has shed light on how cells are able to regenerate protective sheaths around nerve fibres in the brain.
These sheaths, made up of a substance called myelin, are critical for the quick transmission of nerve signals, enabling vision, sensation and movement, but break down in patients with multiple sclerosis (MS).
In multiple sclerosis patients, the protective layer surrounding nerve fibres is stripped away and the nerves are exposed and damaged.
-Dr Veronique Miron(MRC for Regenerative Medicine at the University of Edinburgh)
Macrophages
The study, by the Universities of Edinburgh and Cambridge, found that immune cells, known as macrophages, help trigger the regeneration of myelin.
Researchers found that following loss of or damage to myelin, macrophages can release a compound called activin-A, which activates production of more myelin.
Approved therapies for multiple sclerosis work by reducing the initial myelin injury – they do not promote myelin regeneration. This study could help find new drug targets to enhance myelin regeneration and help to restore lost function in patients with multiple sclerosis.
-Dr Veronique Miron (Medical Council Centre for Regenerative Medicine at the University of Edinburgh)
Study
The study, which looked at myelin regeneration in human tissue samples and in mice, is published in Nature Neuroscience.
It was funded by the MS Society, the Wellcome Trust and the Multiple Sclerosis Society of Canada.
Scientists now plan to start further research to look at how activin-A works and whether its effects can be enhanced.
We urgently need therapies that can help slow the progression of MS and so we’re delighted researchers have identified a new, potential way to repair damage to myelin. We look forward to seeing this research develop further.
-Dr Susan Kohlhaas (Head of Biomedical Research at the MS Society)
We are pleased to fund MS research that may lead to treatment benefits for people living with MS. We look forward to advances in treatments that address repair specifically, so that people with MS may be able to manage the unpredictable symptoms of the disease.
-Dr Karen Lee (Vice-President, Research at the MS Society of Canada
(Source: ed.ac.uk)
Carbon Nanotube Harpoon Catches Individual Brain Cell Signals
Neuroscientists may soon be modern-day harpooners, snaring individual brain-cell signals instead of whales with tiny spears made of carbon nanotubes.
(This image, taken with a scanning electron microscope, shows a new brain electrode that tapers to a point as thick as a single carbon nanotube. Credit: Inho Yoon and Bruce Donald, Duke)
The new brain cell spear is a millimeter long, only a few nanometers wide and harnesses the superior electromechanical properties of carbon nanotubes to capture electrical signals from individual neurons.
"To our knowledge, this is the first time scientists have used carbon nanotubes to record signals from individual neurons, what we call intracellular recordings, in brain slices or intact brains of vertebrates," said Bruce Donald, a professor of computer science and biochemistry at Duke University who helped developed the probe.
He and his collaborators describe the carbon nanotube probes June 19 in PLOS ONE.
"The results are a good proof of principle that carbon nanotubes could be used for studying signals from individual nerve cells," said Duke neurobiologist Richard Mooney, a study co-author. "If the technology continues to develop, it could be quite helpful for studying the brain."
Scientists want to study signals from individual neurons and their interactions with other brain cells to better understand the computational complexity of the brain.
Currently, they use two main types of electrodes, metal and glass, to record signals from brain cells. Metal electrodes record spikes from a population of brain cells and work well in live animals. Glass electrodes also measure spikes, as well as the computations individual cells perform, but are delicate and break easily.
"The new carbon nanotubes combine the best features of both metal and glass electrodes. They record well both inside and outside brain cells, and they are quite flexible. Because they won’t shatter, scientists could use them to record signals from individual brain cells of live animals," said Duke neurobiologist Michael Platt, who was not involved in the study.
In the past, other scientists have experimented with carbon nanotube probes. But the electrodes were thick, causing tissue damage, or they were short, limiting how far they could penetrate into brain tissue. They could not probe inside individual neurons.
To change this, Donald began working on a harpoon-like carbon-nanotube probe with Duke neurobiologist Richard Mooney five years ago. The two met during their first year at Yale in the 1976, kept in touch throughout graduate school and began meeting to talk about their research after they both came to Duke.
Mooney told Donald about his work recording brain signals from live zebra finches and mice. The work was challenging, he said, because the probes and machinery to do the studies were large and bulky on the small head of a mouse or bird.
With Donald’s expertise in nanotechnology and robotics and Mooney’s in neurobiology, the two thought they could work together to shrink the machinery and improve the probes with nano-materials.
To make the probe, graduate student Inho Yoon and Duke physicist Gleb Finkelstein used the tip of an electrochemically sharpened tungsten wire as the base and extended it with self-entangled multi-wall carbon nanotubes to create a millimeter-long rod. The scientists then sharpened the nanotubes into a tiny harpoon using a focused ion beam at North Carolina State University.
Yoon then took the nano-harpoon to Mooney’s lab and jabbed it into slices of mouse brain tissue and then into the brains of anesthetized mice. The results show that the probe transmits brain signals as well as, and sometimes better than, conventional glass electrodes and is less likely to break off in the tissue. The new probe also penetrates individual neurons, recording the signals of a single cell rather than the nearest population of them.
Based on the results, the team has applied for a patent on the nano-harpoon. Platt said scientists might use the probes in a range of applications, from basic science to human brain-computer interfaces and brain prostheses.
Donald said the new probe makes advances in those directions, but the insulation layers, electrical recording abilities and geometry of the device still need improvement.
Engineered stem cell advance points toward treatment for ALS
Transplantation of human stem cells in an experiment conducted at the University of Wisconsin-Madison improved survival and muscle function in rats used to model ALS, a nerve disease that destroys nerve control of muscles, causing death by respiratory failure.
ALS (amyotrophic lateral sclerosis) is sometimes called “Lou Gehrig’s disease.” According to the ALS Association, the condition strikes about 5,600 Americans each year. Only about half of patients are alive three years after diagnosis.
In work recently completed at the UW School of Veterinary Medicine, Masatoshi Suzuki, an assistant professor of comparative biosciences, and his colleagues used adult stem cells from human bone marrow and genetically engineered the cells to produce compounds called growth factors that can support damaged nerve cells.
The researchers then implanted the cells directly into the muscles of rats that were genetically modified to have symptoms and nerve damage resembling ALS.
In people, the motor neurons that trigger contraction of leg muscles are up to three feet long. These nerve cells are often the first to suffer damage in ALS, but it’s unclear where the deterioration begins. Many scientists have focused on the closer end of the neuron, at the spinal cord, but Suzuki observes that the distant end, where the nerve touches and activates the muscle, is often damaged early in the disease.
The connection between the neuron and the muscle, called the neuro-muscular junction, is where Suzuki focuses his attention. “This is one of our primary differences,” Suzuki says. “We know that the neuro-muscular junction is a site of early deterioration, and we suspected that it might be the villain in causing the nerve cell to die. It might not be an innocent victim of damage that starts elsewhere.”
Previously, Suzuki found that injecting glial cell line-derived neurotropic factor (GDNF) at the junction helped the neurons survive. The new study, published in the journal Molecular Therapy on May 28, expands the research to show a similar effect from a second compound, called vascular endothelial growth factor.
In the study, Suzuki found that using stem cells to deliver vascular endothelial growth factor alone improved survival and delayed the onset of disease and the decline in muscle function. That result mirrored his earlier study with GDNF.
But the real advance, Suzuki says, was finding an even better result from using stem cells that create both of these two growth factors. “In terms of disease-free time, overall survival, and sustaining muscle function, we found that delivering the combination was more powerful than either growth factor alone. The results would provide a new hope for people with this terrible disease.”
The new research was supported by the ALS Association, the National Institutes of Health, the University of Wisconsin Foundation, and other groups.
The injected stem cells survived for at least nine weeks, but did not become neurons. Instead, their contribution was to secrete one or both growth factors.
Originally, much of the enthusiasm for stem cells focused on the hope of replacing damaged cells, but Suzuki’s approach is different. “These motor nerve cells have extremely long connections, and replacing these cells is still challenging. But we aim to keep the neurons alive and healthy using the same growth factors that the body creates, and that’s what we have shown here.”
For the test, Suzuki used ALS model rats with a mutation that is found in a small percentage of ALS patients who have a genetic form of the disease. “This model has been accepted as the best test bed for ALS experiments,” says Suzuki.
By using adult mesenchymal stem cells, the technique avoided the danger of tumor that can arise with the transplant of embryonic stem cells and related “do-anything” cells. Importantly, mesenchymal stem cells have been already used in clinical trials for various human diseases.
In the future, Suzuki hopes to apply his approach by using clinical grade stem cells. “Because this is a fatal and untreatable disease, we hope this could enter a clinical trial relatively soon.”
Genetic Predictors of Postpartum Depression Uncovered
Alteration of two genes, detectable by simple blood test during pregnancy, foretold illness with 85 percent certainty in small study
Johns Hopkins researchers say they have discovered specific chemical alterations in two genes that, when present during pregnancy, reliably predict whether a woman will develop postpartum depression.
The epigenetic modifications, which alter the way genes function without changing the underlying DNA sequence, can apparently be detected in the blood of pregnant women during any trimester, potentially providing a simple way to foretell depression in the weeks after giving birth, and an opportunity to intervene before symptoms become debilitating.
The findings of the small study involving 52 pregnant women are described online in the journal Molecular Psychiatry.
“Postpartum depression can be harmful to both mother and child,” says study leader Zachary Kaminsky, Ph.D., an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “But we don’t have a reliable way to screen for the condition before it causes harm, and a test like this could be that way.”
It is not clear what causes postpartum depression, a condition marked by persistent feelings of sadness, hopelessness, exhaustion and anxiety that begins within four weeks of childbirth and can last weeks, several months or up to a year. An estimated 10 to 18 percent of all new mothers develop the condition, and the rate rises to 30 to 35 percent among women with previously diagnosed mood disorders. Scientists long believed the symptoms were related to the large drop-off in the mother’s estrogen levels following childbirth, but studies have shown that both depressed and nondepressed women have similar estrogen levels.
By studying mice, the Johns Hopkins researchers suspected that estrogen induced epigenetic changes in cells in the hippocampus, a part of the brain that governs mood. Kaminsky and his team then created a complicated statistical model to find the candidate genes most likely undergoing those epigenetic changes, which could be potential predictors for postpartum depression. That process resulted in the identification of two genes, known as TTC9B and HP1BP3, about which little is known save for their involvement in hippocampal activity.
Kaminsky says the genes in question may have something to do with the creation of new cells in the hippocampus and the ability of the brain to reorganize and adapt in the face of new environments — two elements important in mood. In some ways, he says, estrogen can behave like an antidepressant, so that when inhibited, it adversely affects mood.
The researchers later confirmed their findings in humans by looking for epigenetic changes to thousands of genes in blood samples from 52 pregnant women with mood disorders. Jennifer L. Payne, M.D., director of the Johns Hopkins Women’s Mood Disorders Center, collected the blood samples. The women were followed both during and after pregnancy to see who developed postpartum depression.
The researchers noticed that women who developed postpartum depression exhibited stronger epigenetic changes in those genes that are most responsive to estrogen, suggesting that these women are more sensitive to the hormone’s effects. Specifically, two genes were most highly correlated with the development of postpartum depression. TTC9B and HP1BP3 predicted with 85 percent certainty which women became ill.
“We were pretty surprised by how well the genes were correlated with postpartum depression,” Kaminsky says. “With more research, this could prove to be a powerful tool.”
Kaminsky says the next step in research would be to collect blood samples from a larger group of pregnant women and follow them for a longer period of time. He also says it would be useful to examine whether the same epigenetic changes are present in the offspring of women who develop postpartum depression.
Evidence suggests that early identification and treatment of postpartum depression can limit or prevent debilitating effects. Alerting women to the condition’s risk factors — as well as determining whether they have a previous history of the disorder, other mental illness and unusual stress — is key to preventing long-term problems.
Research also shows, Kaminsky says, that postpartum depression not only affects the health and safety of the mother, but also her child’s mental, physical and behavioral health.
Kaminsky says that if his preliminary work pans out, he hopes a blood test for the epigenetic biomarkers could be added to the battery of tests women undergo during pregnancy, and inform decisions about the use of antidepressants during pregnancy. There are concerns, he says, about the effects of these drugs on the fetus and their use must be weighed against the potentially debilitating consequences to both the mother and child of foregoing them.
“If you knew you were likely to develop postpartum depression, your decisions about managing your care could be made more clearly,” he says.
(Source: hopkinsmedicine.org)
Researchers find far-reaching, microvascular damage in uninjured side of brain after stroke
While the effects of acute stroke have been widely studied, brain damage during the subacute phase of stroke has been a neglected area of research. Now, a new study by the University of South Florida reports that within a week of a stroke caused by a blood clot in one side of the brain, the opposite side of the brain shows signs of microvascular injury.
Stroke is a leading cause of death and disability in the United States, and increases the risk for dementia.
"Approximately 80 percent of strokes are ischemic strokes, in which the blood supply to the brain is restricted, causing a shortage of oxygen," said study lead author Svitlana Garbuzova-Davis, PhD, associate professor in the USF Department of Neurosurgery and Brain Repair. "Minutes after ischemic stroke, there are serious effects within the brain at both the molecular and cellular levels. One understudied aspect has been the effect of ischemic stroke on the competence of the blood-brain barrier and subsequent related events in remote brain areas."
Using a rat model, researchers at USF Health investigated the subacute phase of ischemic stroke and found deficits in the microvascular integrity in the brain hemisphere opposite to where the initial stroke injury occured.
The study was published in the May 10, 2013 issue of PLOS One.
The USF team found that “diachisis,” a term used to describe certain brain deficits remote from primary insult, can occur during the subacute phase of ischemic stroke. The research discovered diachisis is closely related to a breakdown of the blood-brain barrier, which separates circulating blood from brain tissue.
In the subacute phase of an ischemic stroke, when the stroke-induced disturbances in the brain occur in remote brain microvessels, several areas of the brain are affected by a variety of injuries, including neuronal swelling and diminished myelin in brain structures. The researchers suggest that recognizing the significance of microvascular damage could make the blood-brain barrier (BBB) a therapeutic “target” for future neuroprotective strategies for stroke patients.
The mechanisms of BBB permeability at different phases of stroke are poorly understood. While there have been investigations of BBB integrity and processes in ischemic stroke, the researchers said, most examinations have been limited to the phase immediately after stroke, known as acute stroke. Their interest was in determining microvascular integrity in the brain hemisphere opposite to an initial stroke injury at the subacute phase.
Accordingly, this study using rats with surgically-simulated strokes was designed to investigate the effect of ischemic stroke on the BBB in the subacute phase, and the effects of a compromised BBB upon various brain regions, some distant from the stroke site.
"The aim of this study was to characterize subacute diachisis in rats modeled with ischemic stroke," said co-author Cesar Borlongan, PhD, professor and vice chairman for research in the Department of Neurosurgery and Brain Repair and director of the USF Center for Aging and Brain Repair. "Our specific focus was on analyzing the condition of the BBB and the processes in the areas of the brain not directly affected by ischemia. BBB competence in subacute diachisis is uncertain and needed to be studied."
Their findings suggest that damage to the BBB, and subsequent vascular leakage as the BBB becomes more permeable, plays a major role in subacute diachisis.
The increasing BBB permeability hours after the simulated stroke, and finding that the BBB “remained open” seven days post-stroke, were significant findings, said Dr. Garbuzova-Davis, who is also a researcher in USF Center for Aging and Brain Repair. “Since increased BBB permeability is often associated with brain swelling, BBB leakage may be a serious and life-threatening complication of ischemic stroke.”
Another significant aspect was the finding that autophagy — a mechanism involving cell degradation of unnecessary or dysfunctional cellular components —plays a role in the subacute phase of ischemia. Study results showed that accumulation of numerous autophagosomes within endothelial cells in microvessels of both initially damaged and non-injured brain areas might be closely associated with BBB damage.
Autophagy is a complex but normal process usually aimed at “self-removing” damaged cell components to promote cell survival. It was unclear, however, whether the role of autophagy in subacute post-ischemia was promoting cell survival or cell death.
More than 30 percent of patients who survive strokes develop dementia within two years, the researchers noted.
"Although dementia is complex, vascular damage in post-stroke patients is a significant risk factor, depending on the severity, volume and site of the stroke," said study co-author Dr. Paul Sanberg, USF senior vice president for research and innovation. "Ischemic stroke might initiate neurodegenerative dementia, particularly in the aging population."
The researchers conclude that repair of the BBB following ischemic stroke could potentially prevent further degradation of surviving neurons.
"Recognizing that the BBB is a therapeutic target is important for developing neuroprotective strategies," they said.
New drug enhances radiation treatment for brain cancer in preclinical studies
A novel drug may help increase the effectiveness of radiation therapy for the most deadly form of brain cancer, report scientists at Virginia Commonwealth University Massey Cancer Center. In mouse models of human glioblastoma multiforme (GBM), the new drug helped significantly extend survival when used in combination with radiation therapy.
Recently published in the journal Clinical Cancer Research, the study provides the first preclinical evidence demonstrating that an ATM kinase inhibitor radiosensitizes gliomas. Gliomas are brain tumors that originate from glial cells, which provide support for nerve cells and help regulate the internal environment of the brain. ATM, or ataxia telangiectasia mutated, is an enzyme that helps repair DNA damage. The scientists used an experimental drug, KU-60019, to block the activation of ATM, which led to the enhanced destruction of the gliomas due to their reduced ability to repair the DNA damage caused by the radiation treatment. The new approach was particularly effective against gliomas that have a mutation in the p53 tumor suppressor gene, which accounts for approximately 30 percent of all glioma cases.
"Sadly, the average life expectancy of patients diagnosed with glioblastoma is just 12 to 15 months," says the study’s lead researcher Kristoffer Valerie, Ph.D., co-leader of the Radiation Biology and Oncology research program and a professor in the Department of Radiation Oncology at VCU Massey Cancer Center. "By limiting the tumor’s ability to combat DNA damage caused by treatments such as radiation, we are hopeful that we can enhance our ability to specifically target the glioma, prolong survival and reduce damage to surrounding brain tissue."
Currently, GBM is treated with surgery, followed by chemotherapy and radiation therapy. Potentially, ATM kinase inhibitors like the one used in this study could enhance the effectiveness of some other cancer treatments that kill tumor cells by damaging DNA. The scientists chose radiation therapy in this study since it is already standard care and can be delivered to brain tumors with extreme accuracy, minimizing damage to surrounding healthy tissue.
"If these findings hold up in early phase clinical trials, we expect patients with p53 mutant gliomas to respond well to this treatment while showing few side effects. Also, we anticipate that this same treatment strategy could be effective for other cancers that are treated with DNA-damaging chemotherapies," says Valerie. "We are encouraged by these early findings and will continue to move forward with our research. However, more studies are needed before we can proceed with testing this new therapy in humans."
This first, ‘proof-of-principle’ study is an important follow-up of a study published several years ago on KU-60019 by Valerie and his research team that demonstrated KU-60019’s superior efficacy, specificity and potency on glioma cells as compared to a predecessor ATM inhibitor.
Valerie and his team are conducting additional studies examining the effects of KU-60019 and other ATM kinase inhibitors on gliomas, including studies that combine ATM kinase inhibitors with a type of drug known as a PARP inhibitor to increase the effectiveness of the treatment. PARP inhibitors block the action of poly ADP ribose polymerase (PARP), an enzyme that also aids in the repair of DNA damage. The researchers believe that combining an ATM kinase inhibitor with a PARP inhibitor may cause a condition referred to as “synthetic lethality,” which arises when the functions of at least two interacting genes are simultaneously inhibited, which, in turn, leads to tumor cell death.