Cooling may prevent trauma-induced epilepsy

In the weeks, months and years after a severe head injury, patients often experience epileptic seizures that are difficult to control. A new study in rats suggests that gently cooling the brain after injury may prevent these seizures.

“Traumatic head injury is the leading cause of acquired epilepsy in young adults, and in many cases the seizures can’t be controlled with medication,” says senior author Matthew Smyth, MD, associate professor of neurological surgery and of pediatrics at Washington University School of Medicine in St. Louis. “If we can confirm cooling’s effectiveness in human trials, this approach may give us a safe and relatively simple way to prevent epilepsy in these patients.”

The researchers reported their findings in Annals of Neurology.

Cooling the brain to protect it from injury is not a new concept. Cooling slows down the metabolic activity of nerve cells, and scientists think this may make it easier for brain cells to survive the stresses of an injury. 

Doctors currently cool infants whose brains may have had inadequate access to blood or oxygen during birth. They also cool some heart attack patients to reduce peripheral brain damage when the heart stops beating.

Smyth has been exploring the possibility of using cooling to prevent seizures or reduce their severity.

“Warmer brain cells seem to be more electrically active, and that may increase the likelihood of abnormal electrical discharges that can coalesce to form a seizure,” Smyth says. “Cooling should have the opposite effect.”

Smyth and colleagues at the University of Washington and the University of Minnesota test potential therapies in a rat model of brain injury. These rats develop chronic seizures weeks after the injury.

Researchers devised a headset that cools the rat brain. They were originally testing its ability to stop seizures when they noticed that cooling seemed to be not only stopping but also preventing seizures.

Scientists redesigned the study to focus on prevention. Under the new protocols, they put headsets on some of the rats that cooled their brains by less than 4 degrees Fahrenheit. Another group of rats wore headsets that did nothing. Scientists who were unaware of which rats they were observing monitored them for seizures during treatment and after the headsets were removed.

Rats that wore the inactive headset had progressively longer and more severe seizures weeks after the injury, but rats whose brains had been cooled only experienced a few very brief seizures as long as four months after injury.

Brain injury also tends to reduce cell activity at the site of the trauma, but the cooling headsets restored the normal activity levels of these cells.

The study is the first to reduce injury-related seizures without drugs, according to Smyth, who is director of the Pediatric Epilepsy Surgery program at St. Louis Children’s Hospital.

“Our results show that the brain changes that cause this type of epilepsy happen in the days and weeks after injury, not at the moment of injury or when the symptoms of epilepsy begin,” says Smyth. “If clinical trials confirm that cooling has similar effects in humans, it could change the way we treat patients with head injuries, and for the first time reduce the chance of developing epilepsy after brain injury.”

Smyth and his colleagues have been testing cooling devices in humans in the operating room, and are planning a multi-institutional trial of an implanted focal brain cooling device to evaluate the efficacy of cooling on established seizures.

Why ‘Good Hair’ Matters: The first animal model of recent human evolution reveals that a mutation for thick hair does much more

The first animal model of recent human evolution reveals that a single mutation produced several traits common in East Asian peoples, from thicker hair to denser sweat glands, an international team of researchers reports.

The team, led by researchers from Harvard Medical School, Harvard University, the Broad Institute of MIT and Harvard, Massachusetts General Hospital, Fudan University and University College London, also modeled the spread of the gene mutation across Asia and North America, concluding that it most likely arose about 30,000 years ago in what is today central China. The findings are reported in the cover story of the Feb. 14 issue of Cell.

“This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans,” said Pardis Sabeti, associate professor in the Center for Systems Biology and Department of Organismic and Evolutionary Biology at Harvard University, and one of the paper’s senior authors. Sabeti is also a senior associate member at the Broad Institute.

“This paper tells a story about human evolution in three parts,” said Cliff Tabin, head of the HMS Department of Genetics and co-senior author. “The mouse model links multiple traits to a single mutation, the related association study finds these traits in humans, and computer models tell us where and when the mutation likely arose and spread.”

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In research, it matters whether you’re a man or a mouse

Mice are poor stand-ins for people in experiments on some types of inflammation, a new study concludes. But some scientists say that critique discounts the value of mouse studies, many of which simply couldn’t be done without the animals.

More attention — and money — should go toward studying disease in people than on mouse research, a consortium of scientists contends online February 11 in the Proceedings of the National Academy of Sciences. Too often, researchers make a discovery in mice and assume that humans will react in the same way, says study coauthor Ronald Tompkins, chief of the Massachusetts General Hospital burn service. “The presumption is not justifiable,” he says. As a result, drug trials — often based heavily on data gleaned from studies with mice — can fail. 

But other scientists say that critique isn’t new and is overstated. Clinical trials are unsuccessful for many reasons, says Derry Roopenian, an immunologist and mouse geneticist at the Jackson Laboratory in Bar Harbor, Maine. “There’s frailty all along the process. That’s not a failure of the mouse.”

He and other critics worry that the study, conducted with a generic strain of laboratory mouse called Black6, unfairly tarnishes the reputation of all mice, even ones engineered to be as much like humans as possible. The group’s conclusions, were they accepted by policy makers, could set back biomedical research by jeopardizing funding for mouse studies, critics warn. “Without the mouse, progress is going to be slowed to a standstill,” Roopenian says.

Most of the researchers agree that creating mice with biologic responses that more closely mirror humans is important to understand diseases and develop new drugs. The sticking point appears to be how to balance mouse-based research with research involving humans.

Old drug may point the way to new treatments for diabetes and obesity

Researchers at the University of Michigan’s Life Sciences Institute have found that amlexanox, an off-patent drug currently prescribed for the treatment of asthma and other uses, also reverses obesity, diabetes and fatty liver in mice.

The findings from the lab of Alan Saltiel, the Mary Sue Coleman director of the Life Sciences Institute, were published online Feb. 10 in the journal Nature Medicine.

"One of the reasons that diets are so ineffective in producing weight loss for some people is that their bodies adjust to the reduced calories by also reducing their metabolism, so that they are ‘defending’ their body weight," Saltiel said. "Amlexanox seems to tweak the metabolic response to excessive calorie storage in mice."

Different formulations of amlexanox are currently prescribed to treat asthma in Japan and canker sores in the United States. Saltiel is teaming up with clinical-trial specialists at U-M to test whether amlexanox will be useful for treating obesity and diabetes in humans. He is also working with medicinal chemists at U-M to develop a new compound based on the drug that optimizes its formula.

The study appears to confirm and extend the notion that the genes IKKE and TBK1 play a crucial role for maintaining metabolic balance, a discovery published by the Saltiel lab in 2009 in the journal Cell.

"Amlexanox appears to work in mice by inhibiting two genes—IKKE and TBK1—that we think together act as a sort of brake on metabolism," Saltiel said. "By releasing the brake, amlexanox seems to free the metabolic system to burn more, and possibly store less, energy."

UAB researchers cure type 1 diabetes in dogs

Researchers from the Universitat Autònoma de Barcelona (UAB), led by Fàtima Bosch, have shown for the first time that it is possible to cure diabetes in large animals with a single session of gene therapy. As published this week in Diabetes, the principal journal for research on the disease, after a single gene therapy session, the dogs recover their health and no longer show symptoms of the disease. In some cases, monitoring continued for over four years, with no recurrence of symptoms.

The therapy is minimally invasive. It consists of a single session of various injections in the animal’s rear legs using simple needles that are commonly used in cosmetic treatments. These injections introduce gene therapy vectors, with a dual objective: to express the insulin gene, on the one hand, and that of glucokinase, on the other. Glucokinase is an enzyme that regulates the uptake of glucose from the blood. When both genes act simultaneously they function as a “glucose sensor”, which automatically regulates the uptake of glucose from the blood, thus reducing diabetic hyperglycemia (the excess of blood sugar associated with the disease).

As Fàtima Bosch, the head researcher, points out, “this study is the first to demonstrate a long-term cure for diabetes in a large animal model using gene therapy.”

This same research group had already tested this type of therapy on mice, but the excellent results obtained for the first time with large animals lays the foundations for the clinical translation of this gene therapy approach to veterinary medicine and eventually to diabetic patients.

The study was led by the head of the UAB’s Centre for Animal Biotechnology and Gene Therapy (CBATEG) Fàtima Bosch, and involved the Department of Biochemistry and Molecular Biology of the UAB, the Department of Medicine and Animal Surgery of the UAB, the Faculty of Veterinary Science of the UAB, the Department of Animal Health and Anatomy of the UAB, the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), the Children’s Hospital of Philadelphia (USA) and the Howard Hughes Medical Institute of Philadelphia (USA).

The brain circuit that makes it hard for obese people to lose weight

Imagine you are driving a car, and the harder you press on the accelerator, the harder an invisible foot presses on the brake. That’s what happens when obese people diet – the less food they eat, the less energy they burn, and the less weight they lose.

While this phenomenon is known, scientists at Sydney’s Garvan Institute of Medical Research and the University of NSW have pinpointed the exact brain circuitry behind it and have published their findings in the prestigious international journal Cell Metabolism, now online.

Dr Shu Lin, Dr Yanchuan Shi and Professor Herbert Herzog and his team have been studying the complex processes behind energy balance using various mouse models. They have shown that the neurotransmitter Neuropeptide Y (NPY), known for stimulating appetite, also plays a major role in controlling whether the body burns or conserves energy.

The researchers found that NPY produced in a particular region of the brain – the arcuate nucleus (Arc) of the hypothalamus – inhibits the activation of ‘brown fat’, one of the primary tissues where the body generates heat.

“This study is the first to identify the neurotransmitters and neural pathways that carry signals generated by NPY in the brain to brown fat cells in the body. It is also the first to show a direct connection between Arc NPY, the sympathetic nervous system and the control of energy expenditure.” said Professor Herzog.

“We know that NPY also influences other aspects of the sympathetic nervous system – such as heart rate and gut function – but its control of heat generation through brown fat seems to be the most critical factor in the control of energy expenditure.”

“When you don’t eat, or dramatically curtail your calorie intake, levels of NPY rise sharply. High levels of NPY signal to the body that it is in ‘starvation mode’ and should try to replenish and conserve as much energy as possible. As a result, the body reduces processes that are not absolutely necessary for survival.”

“Evolution has provided us with these mechanisms to help us survive famine, and they are strictly controlled. When people had to survive by finding food or hunting game, they could not afford to run out of energy and die of exhaustion, so their bodies evolved to cope.”

“Until the twentieth century, there were no fast food chains and people did not have ready access to high fat, high sugar, foods. So in evolutionary terms, it was unlikely that people were going to get very fat and mechanisms were only put in place to prevent you losing weight.”

“Obesity is a modern epidemic, and the challenge will be to find ways of tricking the body into losing weight – and that will mean somehow circumventing or manipulating this NPY circuit, probably with drugs.”

Chemical reaction keeps stroke-damaged brain from repairing itself

Nitric oxide, a gaseous molecule produced in the brain, can damage neurons. When the brain produces too much nitric oxide, it contributes to the severity and progression of stroke and neurodegenerative diseases such as Alzheimer’s. Researchers at Sanford-Burnham Medical Research Institute recently discovered that nitric oxide not only damages neurons, it also shuts down the brain’s repair mechanisms. Their study was published by the Proceedings of the National Academy of Sciences the week of February 4.

“In this study, we’ve uncovered new clues as to how natural chemical reactions in the brain can contribute to brain damage—loss of memory and cognitive function—in a number of diseases,” said Stuart A. Lipton, M.D., Ph.D., director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center and a clinical neurologist.

Lipton led the study, along with Sanford-Burnham’s Tomohiro Nakamura, Ph.D., who added that these new molecular clues are important because “we might be able to develop a new strategy for treating stroke and other disorders if we can find a way to reverse nitric oxide’s effect on a particular enzyme in nerve cells.”

Nitric oxide inhibits the neuroprotective ERK1/2 signaling pathway

Learning and memory are in part controlled by NMDA-type glutamate receptors in the brain. These receptors are linked to pores in the nerve cell membrane that regulate the flow of calcium and sodium in and out of the nerve cells. When these NMDA receptors get over-activated, they trigger the production of nitric oxide. In turn, nitric oxide attaches to other proteins via a reaction called S-nitrosylation, which was first discovered by Lipton and colleagues. When those S-nitrosylated proteins are involved in cell survival and lifespan, nitric oxide can cause brain cells to die prematurely—a hallmark of neurodegenerative disease.

In their latest study, Lipton, Nakamura and colleagues used cultured neurons as well as a living mouse model of stroke to explore nitric oxide’s relationship with proteins that help repair neuronal damage. They found that nitric oxide reacts with the enzyme SHP-2 to inhibit a protective cascade of molecular events known as the ERK1/2 signaling pathway. Thus, nitric oxide not only damages neurons, it also blocks the brain’s ability to self-repair.

What’s Your Fish Thinking?

Studying the links between brain and behavior may have just gotten easier. For the first time, neuroscientists have found a way to watch neurons fire in an independently moving animal. Though the study was done in fish, it may hold clues to how the human brain works.

"This technique will really help us understand how we make sense of the world and why we behave the way we do," says Martin Meyer, a neuroscientist at King’s College London who was not involved in the work.

The study was carried out in zebrafish, a popular animal model because they’re small and easy to breed. More important, zebrafish larvae are transparent, which gives scientists an advantage in identifying the neural circuits that make them tick. Yet, under a typical optical microscope, neurons that are active and firing look much the same as their quieter counterparts. To see what neurons are active and when, neuroscientists have therefore developed a variety of indicators and dyes. For example, when a neuron fires, it is flooded with calcium ions, which can cause some of the dyes to light up.

Still, the approach has limitations. Traditionally, Meyer explains, researchers would immobilize the head or entire body of a zebrafish larvae so that they could get a clearer picture of what was happening inside the brain. Even so, it was difficult to interpret neural activity for just a few neurons and over a short period of time. Researchers needed a better way to study the zebrafish brain in real time.

Enter Junichi Nakai of Saitama University’s Brain Science Institute in Japan. He and colleagues selected a glowing marker known as green fluorescent protein (GFP) and linked it to a compound that would light up in the presence of large amounts of calcium. The researchers then inserted the DNA that codes for this marker into the zebrafish genome, tying it to a specific protein only found in neurons. This means that only actively firing neurons would fluoresce, and scientists could track neural activity without applying dye. Because the signal was stronger and clearer, researchers didn’t have to immobilize the larvae.

To test the setup, Nakai and colleagues sent the genetically engineered zebrafish larvae hunting for food. When the larvae see a swimming single-celled animal called a paramecium, they engage in what animal behaviorists call a prey capture response: They turn their heads toward the paramecium, swim at it, and finally eat it.

Using their newly developed imaging system, Nakai and colleagues associated the sight of moving paramecium and prey capture behavior with the activation of a group of neurons in the optic tectum, the visual center of the zebrafish brain. The neurons pulsed in tandem with the movements of the paramecium—a sudden dart of the one-celled organism caused a bright flash of neural activity in the zebrafish tectum. The tectum went silent if the paramecium stilled. Only moving prey interested the larvae, the team reports today in Current Biology. These particular neurons, Nakai proposes, are part of a specific visual-motor pathway that links the sight of moving prey with swimming behavior.

"It’s a good proof of principle study," Meyer says. "The most important thing is that they showed [the technique worked] on freely behaving fish."

Scientists Uncover a Previously Unknown Mechanism of Memory Formation

It takes a lot to make a memory. New proteins have to be synthesized, neuron structures altered. While some of these memory-building mechanisms are known, many are not. Some recent studies have indicated that a unique group of molecules called microRNAs, known to control production of proteins in cells, may play a far more important role in memory formation than previously thought.

Now, a new study by scientists on the Florida campus of The Scripps Research Institute has for the first time confirmed a critical role for microRNAs in the development of memory in the part of the brain called the amygdala, which is involved in emotional memory. The new study found that a specific microRNA—miR-182—was deeply involved in memory formation within this brain structure.

“No one had looked at the role of microRNAs in amygdala memory,” said Courtney Miller, a TSRI assistant professor who led the study. “And it looks as though miR-182 may be promoting local protein synthesis, helping to support the synapse-specificity of memories.”

In the new study, published in the Journal of Neuroscience, the scientists measured the levels of all known microRNAs following an animal model of learning. A microarray analysis, which enables rapid genetic testing on a large scale, showed that more than half of all known microRNAs are expressed in the amygdala. Seven of those microRNAs increased and 32 decreased when learning occurred.

The study found that, of the microRNAs expressed in the brain, miR-182 had one of the lowest levels and these decreased further with learning. Despite these very low levels, its overexpression prevented the formation of memory and led to a decrease in proteins that regulate neuronal plasticity (neurons’ ability to adapt) through changes in structure.

These findings suggest that learning-induced suppression of miR-182 is a main supporting factor in the formation of long-term memory in the amagdala, as well as an underappreciated mechanism for regulating protein synthesis during memory consolidation, Miller said.

Further analysis identified miR-182 as a repressor of proteins that control actin—a major component of the cytoskeleton, the scaffolding that holds cells together.

“We know that memory formation requires changes in dendritic spines on the neurons through regulation of the actin cytoskeleton,” Miller said. “When miR-182 is suppressed through learning it halts, at least in part, repression of actin-regulating proteins, so there’s a good chance that miR-182 exerts important control over the actin cytoskeleton.”

Miller is now interested in whether or not high levels of miR-182 accumulate in the aging brain, something that would help to explain a tendency toward memory loss in the elderly. She also notes that other research has shown that animal models lacking miR-182 had no significant physical or cellular abnormalities, suggesting that miR-182 could be a viable target for drug discovery.

(Image: stockfresh)