Posts tagged glutamate
Articles and news from the latest research reports.
Unprecedented structural insights reveal how NMDA receptors can be blocked, to limit neurotoxicity
Structural biologists at Cold Spring Harbor Laboratory (CSHL) and collaborators at Emory University have obtained important scientific results likely to advance efforts to develop new drugs targeting NMDA receptors in the brain.
NMDA (N-methyl D-aspartate) receptors are found on the surface of many nerve cells and are involved in signaling that is essential in basic brain functions including learning and memory formation. Problems with their function have been implicated in depression, schizophrenia, Alzheimer’s and Parkinson’s diseases, as well as brain damage caused by stroke.
Normally, NMDA receptors are activated by glutamate, the most common neurotransmitter of excitatory cell-to-cell messages in the brain.
Overactivation of NMDA receptors is a known cause of nerve-cell toxicity. Thus, drug developers have long sought compounds that can selectively block or antagonize NMDA receptors, while not affecting other types of glutamate receptors in the brain, whose function is essential.
However, a basic question — how those compounds bind and antagonize NMDA receptors — has not been understood at the molecular level.
Over a period of years, CSHL Associate Professor Hiro Furukawa and colleagues have taken a step-by-step approach to learn about the precise shape of various subunits of the complex NMDA receptor protein, and demonstrating the relationship between different versions of the receptor’s shape and its function. (see more here) Since the subunits have different biological roles, they have to be specifically targeted by drug compounds to obtain specific effects.
Furukawa’s team has used a technique called x-ray crystallography to map various domains of the protein while it is bound to different chemical compounds, or antagonists, that downregulate its function. Today in the journal Neuron they publish the first crystal structures of two NMDA receptor subunits (called GluN1 and GluN2A) in complex with four different compounds known to have the capacity to inhibit, or antagonize, NMDA receptor function.
Showing this two-unit ligand binding domain (LBD) in complex with NMDA antagonists — potential drugs — reveals that each antagonist has a distinctive mode of binding the LBD. In essence, the “docking port” is held open, but to a different extent when different antagonists are bound. The study also reveals an element in the antagonist binding site that is only present in GluN2A subunit, but not in the others. This previously hidden information, says Furukawa, is critical: “It indicates different strategies to develop therapeutic compounds – ones that bind to a certain type of NMDA receptors very specifically. Being able to target specific subtypes of the receptor is of enormous interest and has great therapeutic potential in a range of illnesses and injuries affecting the brain.”
Dietary Amino Acids Relieve Sleep Problems after Traumatic Brain Injury in Animals
Scientists who fed a cocktail of key amino acids to mice improved sleep disturbances caused by brain injuries in the animals. These new findings suggest a potential dietary treatment for millions of people affected by traumatic brain injury (TBI)—a condition that is currently untreatable.
“If this type of dietary treatment is proved to help patients recover function after traumatic brain injury, it could become an important public health benefit,” said study co-leader Akiva S. Cohen, Ph.D., a neuroscientist at The Children’s Hospital of Philadelphia (CHOP).
Cohen is the co-senior author of the animal TBI study appearing today in Science Translational Medicine. He collaborated with two experts in sleep medicine: co-senior author Allan I. Pack, M.D., Ph.D., director of the Center for Sleep and Circadian Neurobiology in the Perelman School of Medicine at the University of Pennsylvania; and first author Miranda M. Lim, M.D., Ph.D., formerly at the Penn Sleep Center, and now on faculty at the Portland VA Medical Center and Oregon Health and Science University.
Every year in the U.S., an estimated 2 million people suffer a TBI, accounting for a major cause of disability across all age groups. Although 75 percent of reported TBI cases are milder forms such as concussion, even concussion may cause chronic neurological impairments, including cognitive, motor and sleep problems.
“Sleep disturbances, such as excessive daytime sleepiness and nighttime insomnia, disrupt quality of life and can delay cognitive recovery in patients with TBI,” said Lim, a neurologist and sleep medicine specialist. Although physicians can relieve the dangerous swelling that occurs after a severe TBI, there are no existing treatments to address the underlying brain damage associated with neurobehavioral problems such as impaired memory, learning and sleep patterns.
Cohen and team investigate the use of selected branched chain amino acids (BCAA)—precursors of the neurotransmitters glutamate and GABA, which are involved in communication among neurons and help to maintain a normal balance in brain activity. His research team previously showed that a BCAA diet restored cognitive ability in brain-injured mice. The current study was the first to analyze sleep-wake patterns in an animal model.
Comparing mice with experimentally induced mild TBI to uninjured mice, the scientists found the injured mice were unable to stay awake for long periods of time. The injured mice had lower activity among orexin neurons, which help to maintain the animals’ wakefulness. This is similar to results in human studies showing decreased orexin levels in the spinal fluid after TBI.
In the current study, the dietary therapy restored the orexin neurons to a normal activity level and improved wakefulness in the brain-injured mice. EEG recordings also showed improved brain wave patterns among the mice that consumed the BCAA diet.
“These results in an animal model provide a proof-of-principle for investigating this dietary intervention as a treatment for TBI patients,” said Cohen. “If a dietary supplement can improve sleeping and waking patterns as well as cognitive problems, it could help brain-injured patients regain crucial functions.” Cohen cautioned that current evidence does not support TBI patients medicating themselves with commercially available amino acids.
(Source: chop.edu)
New study shows promise for first effective medicine to treat cocaine dependence
New research published in JAMA Psychiatry reveals that topiramate, a drug approved by the U.S. Food and Drug Administration (FDA) to treat epilepsy and migraine headaches, also could be the first reliable medication to help treat cocaine dependence.
The study, led by Bankole A. Johnson, DSc. MD., MB.ChB., MPhil., chairman of the Department of Psychiatry at the University of Maryland School of Medicine and head of the School’s new Brain Science Research Consortium Unit, with support from the National Institutes of Health and Agency for Healthcare Research and Quality, is one of the first to establish a pharmacological treatment for cocaine addiction, for which there are currently no FDA-approved medications.
Addiction affects 13.2 to 19.7 million cocaine users worldwide. Cocaine is responsible for more U.S. emergency room visits than any other illegal drug. Cocaine harms the brain, heart, blood vessels, and lungs — and can even cause sudden death.
Professor Johnson, one of the nation’s leading neuroscientists and psychopharmacologists, had previously found that topiramate was a safe and effective treatment for alcohol dependence compared with placebo.
In releasing the new study, Professor Johnson, who conducted the research when he was with Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia, provided full disclosures, which follow the text of this news announcement.*
The study enrolled 142 participants, aged 18 years or older, seeking treatment for cocaine dependence. Following enrollment, participants were randomly assigned into a topiramate group or placebo group. Neither the participants nor the healthcare professionals administering the treatment knew who was in which group (double-blinded study).
Using an intent-to-treat analysis, the researchers found that topiramate was more efficacious than placebo at increasing the participants’ weekly proportion of cocaine nonuse days and in increasing the likelihood that participants would have cocaine-free weeks. Furthermore, compared with placebo, topiramate also was significantly associated with a decrease in craving for cocaine and an improvement in participants’ global functioning.
The study investigators also observed few side effects due to drug treatment. In general, participants in the topiramate group experienced mild side-effects, including abnormal tingling skin sensations, taste distortions, anorexia, and difficulty concentrating.
"Our findings reveal that topiramate is a safe and robustly efficacious medicine for the treatment of cocaine dependence, and has the potential to make a major contribution to the global health crisis of addiction," Professor Johnson said. "However, topiramate treatment also is associated with glaucoma, and higher doses of the drug can increase the risk of side effects; therefore, caution must be exercised when prescribing the drug, especially when given in high doses."
These results build upon earlier work from Professor. Johnson’s group which indicated that individuals dependent on cocaine, but not seeking treatment, who took topiramate were more likely to experience reduced cravings and preference for cocaine, compared with placebo. The findings of the current study indicate that topiramate may be even more effective in treating people with addiction who actively want to quit using cocaine.
"Because topiramate is the first medication to demonstrate a robust therapeutic effect for the treatment of cocaine or alcohol dependence, its fundamental neurochemical effects provide important clues as to common links in the neurobiological basis of the addictive process in general," remarked Professor Johnson. "These findings also add to our understanding of how addiction affects the brain because it demonstrates the unique concept that dual neurotransmitter modulation, by simultaneously augmenting the inhibitory action of gamma amino butyric acid and inhibiting the excitatory effects of glutamate, can result in therapeutic effects that reduce the propensity to use cocaine."
*Editor’s Notes:
A. Statement of Disclosure
Professor Johnson reported serving as a consultant for Johnson & Johnson (Ortho-McNeil Janssen Scientific Affairs, LLC) the manufacturer of topiramate, from 2003-2008 and currently has no affiliation with that Company, Transcept Pharmaceuticals, Inc. from 2006-2008, Eli Lilly and Company from 2009-2010, and Organon from 2007-2010. He currently consults for D&A Pharma, ADial Pharmaceuticals, LLC, (with which he also serves as chairman), and Psychological Education Publishing Company (PEPCo), LLC. Topiramate is currently available as a generic medicine in the USA, and Professor Johnson has no commercial affiliation with any generic manufacturer of topiramate. Dr. Liu reported serving as a consultant for Celladon Corporation. No other disclosures were reported.
B. Funding/ Support
This study was supported by NIH grants 501 DAO17296-04 and 5 RC1AA019274-02, and Agency for Healthcare Research and Quality grant 7 RO1 HS020263092.
Child neurologist finds potential route to better treatments for Fragile X, autism
When you experience something, neurons in the brain send chemical signals called neurotransmitters across synapses to receptors on other neurons. How well that process unfolds determines how you comprehend the experience and what behaviors might follow. In people with Fragile X syndrome, a third of whom are eventually diagnosed with Autism Spectrum Disorder, that process is severely hindered, leading to intellectual impairments and abnormal behaviors.
In a study published in the online journal PLoS One, a team of UNC School of Medicine researchers led by pharmacologist C.J. Malanga, MD, PhD, describes a major reason why current medications only moderately alleviate Fragile X symptoms. Using mouse models, Malanga discovered that three specific drugs affect three different kinds of neurotransmitter receptors that all seem to play roles in Fragile X. As a result, current Fragile X drugs have limited benefit because most of them only affect one receptor.
Nearly one million people in the United States have Fragile X Syndrome, which is the result of a single mutated gene called FMR1. In people without Fragile X, the gene produces a protein that helps maintain the proper strength of synaptic communication between neurons. In people with Fragile X, FMR1 doesn’t produce the protein, the synaptic connection weakens, and there’s a decrease in synaptic input, leading to mild to severe learning disabilities and behavioral issues, such as hyperactivity, anxiety, and sensitivity to sensory stimulation, especially touch and noise.
More than two decades ago, researchers discovered that – in people with mental and behavior problems – a receptor called mGluR5 could not properly regulate the effect of the neurotransmitter, glutamate. Since then, pharmaceutical companies have been trying to develop drugs that target glutamate receptors. “It’s been a challenging goal,” Malanga said. “No one so far has made it work very well, and kids with Fragile X have been illustrative of this.”
But there are other receptors that regulate other neurotransmitters in similar ways to mGluR5. And there are drugs already available for human use that act on those receptors. So Malanga’s team checked how those drugs might affect mice in which the Fragile X gene has been knocked out.
By electrically stimulating specific brain circuits, Malanga’s team first learned how the mice perceived reward. The mice learned very quickly that if they press a lever, they get rewarded via a mild electrical stimulation. Then his team provided a drug molecule that acts on the same reward circuitry to see how the drugs affect the response patterns and other behaviors in the mice.
His team studied one drug that blocked dopamine receptors, another drug that blocked mGluR5 receptors, and another drug that blocked mAChR1, or M1, receptors. Three different types of neurotransmitters – dopamine, glutamate, and acetylcholine – act on those receptors. And there were big differences in how sensitive the mice were to each drug.
“Turns out, based on our study and a previous study we did with my UNC colleague Ben Philpot, that Fragile X mice and Angelman Syndrome mice are very different,” Malanga said. “And how the same pharmaceuticals act in these mouse models of Autism Spectrum Disorder is very different.”
Malanga’s finding suggests that not all people with Fragile X share the same biological hurdles. The same is likely true, he said, for people with other autism-related disorders, such as Rett syndrome and Angelman syndrome.
“Fragile X kids likely have very different sensitivities to prescribed drugs than do other kids with different biological causes of autism,” Malanga said.
(Source: news.unchealthcare.org)
Researchers develop new model to study schizophrenia and other neurological conditions
Schizophrenia is one of the most devastating neurological conditions, with only 30 percent of sufferers ever experiencing full recovery. While current medications can control most psychotic symptoms, their side effects can leave individuals so severely impaired that the disease ranks among the top ten causes of disability in developed countries.
Now, in this week’s issue of the Proceedings of the National Academy of Sciences, Thomas Albright and Ricardo Gil-da-Costa of the Salk Institute for Biological Studies describe a model system that completes the bridge between cellular and human studies of schizophrenia, an advance that should help speed the development of therapeutics for schizophrenia and other neurological disorders.
"Part of the terror of schizophrenia is that the brain can’t properly integrate sensory information, so the world is a disorientating series of unrelated bits of input," says Albright, the Conrad T. Prebys Chair in Vision Research. "We’ve created a model that tests the ability to do sensory integration, which should be extremely useful for pharmaceutical research."
Currently, over 1.1 percent of the world’s population has schizophrenia, with an estimated three million individuals in the United States alone. The economic cost is high: In 2002, Americans spent nearly $63 billion on treatment and managing disability. The emotional cost is higher still: Ten percent of those with schizophrenia are driven to commit suicide by the burden of coping with the disease.
Initially, it was thought that excessive amounts of the neurotransmitter dopamine caused psychotic symptoms, and indeed, current anti-psychotic drugs work by blocking dopamine from entering brain cells. But nearly all of these drugs have severe cognitive side effects, which led researchers to speculate that some other mechanism must also be involved.
A major clue to understanding schizophrenia came with the development of phencyclidine (PCP) in 1956. It was intended to keep patients safely asleep during surgeries, but many woke up with symptoms similar to those experienced by people with schizophrenia, including hallucinations and the disorientation of feeling “dissociated” from their limbs, resulting in PCP being abandoned for clinical purposes. A decade later, it was replaced by a derivative called ketamine. At doses high enough to put patients to sleep, ketamine is an effective anesthetic. At lower doses, it temporarily produces the same schizophrenia-like effects as PCP.
The two drugs are part of a class called N-methyl-D-aspartate receptor antagonists. Essentially, they work by gumming up the mechanism by which glutamate, the main excitatory neurotransmitter, would enter brain cells. Thus, it is clear that dopamine dysfunction accounts for some of the symptoms of psychosis, although that is probably not the full story.
"While dopamine has limited reach in the brain, any dysfunction in glutamate would be expected to have the sort of widespread effects we see in the perceptual disorders associated with schizophrenia," says Albright. "Nevertheless, which neurotransmitter was primary to these disorders—glutamate or dopamine—has been argued about for years."
Standing in the way of a definitive answer was a researcher’s Catch-22: Many experiments designed to understand cognitive disorders such as schizophrenia or Alzheimer’s require a participant’s conscious attention-yet these disorders interfere with attention.
To get around this, scientists turned to electroencephalograms (EEGs), which can be used to detect changes in cases where a subject is not consciously paying attention to a stimulus, by recording the brain’s electrical signals through electrodes placed in a scalp cap. In one test, a series of tones is played, but an “oddball” tone breaks the pattern in the sequence. A healthy brain can still easily spot the differences, even if a participant is concentrating on another task, such as reading a magazine.
"The test works because the brain is a prediction machine-it’s built to anticipate what should come next," says Albright. "If you have healthy working memory, you should be able to perceive a pattern and notice when something violates it, but patients suffering from some mental health disorders lack that basic ability."
In their latest research, Albright’s team detected the difference through two signals, event-related brain potentials called mismatch negativity (MMN) and P3. The MMN reflects differential brain activity to the detected oddball tone, below the level of conscious awareness. P3 picks up the next phase: a subject’s attention orientation to the oddball tone.
Still, a gap in understanding remained. While scientists could do cellular work in animal models on the role of dopamine versus glutamate, and they could do EEGs in human beings, a bridge between the two remained elusive. Such a bridge can help scientists understanding of how healthy and disordered brains work from the cellular level all the way to the multiple interactions between brain areas. Moreover, it can enable pre-clinical and clinical trials linking cellular and systems levels for successful therapeutic avenues.
Gil-da-Costa has at last crossed the bridge by crafting the first non-invasive scalp EEG setup that records accurately from the brains of non-human primates, with the same proportional density of electrodes as a human cap and no distortions in signal caused by an incorrect fit. This setup allows him to get accurate measurements of MMN and P3, with the same protocols that are followed in humans. As a result, the lab has come closer than ever before to untangling the roles of dopamine and glutamate.
"While rodents are essential for understanding mechanisms at a cellular or molecular level, at a higher cognitive level, the best you could do was a sort of rough analogy. Now, finally, we can have a one-to-one correspondence," says Gil-da-Costa. "For sensory integration, our findings with this model support the glutamate hypothesis."
Pharmaceutical companies are interested in the model, because of the potential for more precise testing and the universality of the MMN/P3 assays. “These brain makers are the same across dozens of neurological diseases, as well as brain trauma, so you can test potential therapies not just for schizophrenia, but for conditions such as Parkinson’s, Alzheimer’s, bi-polar disorder, and traumatic brain injuries,” says Gil-da-Costa. “We hope this will help begin a new era in neurological therapeutics.”
(Source: salk.edu)
Head hurts? Zap the wonder nerve in your neck
"It was like red-hot pokers needling one side of my face," says Catherine, recalling the cluster headaches she experienced for six years. "I just wanted it to stop." But it wouldn’t – none of the drugs she tried had any effect.
Thinking she had nothing to lose, last year she enrolled in a pilot study to test a handheld device that applies a bolt of electricity to the neck, stimulating the vagus nerve – the superhighway that connects the brain to many of the body’s organs, including the heart.
The results of the trial were presented last month at the International Headache Congress in Boston, and while the trial is small, the findings are positive. Of the 21 volunteers, 18 reported a reduction in the severity and frequency of their headaches, rating them, on average, 50 per cent less painful after using the device daily and whenever they felt a headache coming on.
This isn’t the first time vagal nerve stimulation has been used as a treatment – but it is one of the first that hasn’t required surgery. Some people with epilepsy have had a small generator that sends regular electrical signals to the vagus nerve implanted into their chest. Implanted devices have also been approved to treat depression. What’s more, there is increasing evidence that such stimulation could treat many more disorders from headaches to stroke and possibly Alzheimer’s disease.
The latest study suggests it is possible to stimulate the nerve through the skin, rather than resorting to surgery. “What we’ve done is figured out a way to stimulate the vagus nerve with a very similar signal, but non-invasively through the neck,” says Bruce Simon, vice-president of research at New Jersey-based ElectroCore, makers of the handheld device. “It’s a simpler, less invasive way to stimulate the nerve.”
Cluster headaches are thought to be triggered by the overactivation of brain cells involved in pain processing. The neurotransmitter glutamate, which excites brain cells, is a prime suspect. ElectroCore turned to the vagus nerve as previous studies had shown that stimulating it in people with epilepsy releases neurotransmitters that dampen brain activity.
When the firm used a smaller version of ElectroCore’s device on rats, it found it reduced glutamate levels and excitability in these pain centres. Other studies have shown that vagus nerve stimulation causes the release of inhibitory neurotransmitters which counter the effects of glutamate.
The big question is whether a non-implantable device can really trigger changes in brain chemistry in humans, or whether people are simply experiencing a placebo effect. “The vagus nerve is buried deep in the neck, and something that’s delivering currents through the skin can only go so deep,” says Mike Kilgard of the University of Texas at Dallas. As you turn up the voltage, there’s a risk of it activating muscle fibres that trigger painful cramps, he adds.
Simon says that volunteers using the device haven’t reported any serious side effects. He adds that ElectroCore will soon publish data showing changes in brain activity in humans after using the device. Placebo-controlled trials are also about to start.
Catherine has been using it for a year without ill effect. “I can now function properly as a human being again,” she says.
The many uses of the wonder nerve
Coma, irritable bowel syndrome, asthma and obesity are just some of the disparate conditions that vagus nerve stimulation may benefit and for which human trials are under way.
It might also help people with tinnitus. Although people with tinnitus complain of ringing in their ears, the problem actually arises because too many neurons fire in the auditory part of the brain when certain frequencies are heard.
Mike Kilgard of the University of Texas at Dallas reasoned that if people were played tones that didn’t trigger tinnitus while the vagus nerve was stimulated, this might coax the rogue neurons into firing in response to these frequencies instead. “By activating this nerve we can enhance the brain’s ability to rewire itself,” he says.
He has so far tested the method in rats and in 10 people with tinnitus, using an implanted device to stimulate the nerve. Not everyone noticed an improvement, but even so Kilgard is planning a larger trial. The work was presented at a meeting of the International Union of Physiological Sciences in Birmingham, UK, last month. The technique is also being tested in people who have had a stroke.
"If these studies stand up it could be worth changing the name of the vagus nerve to the wonder nerve," says Sunny Ogbonnaya at Cork University Hospital in Ireland.
New Insight Into How Brain ‘Learns’ Cocaine Addiction
A team of researchers says it has solved the longstanding puzzle of why a key protein linked to learning is also needed to become addicted to cocaine. Results of the study, published in the Aug. 1 issue of the journal Cell, describe how the learning-related protein works with other proteins to forge new pathways in the brain in response to a drug-induced rush of the “pleasure” molecule dopamine. By adding important detail to the process of addiction, the researchers, led by a group at Johns Hopkins, say the work may point the way to new treatments.
“The broad question was why and how cocaine strengthened certain circuits in the brain long term, effectively re-wiring the brain for addiction,” says Paul Worley, M.D., a professor in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine. “What we found in this study was how two very different types of systems in the brain work together to make that happen.” Cocaine addiction, experts say, is among the strongest of addictions.
Worley did not come to the problem as an addiction researcher, but as an expert in a group of genes known as immediate early genes, which rapidly ramp up production in neurons when the brain is exposed to new information. In 2001, he said, a European group led by François Conquet of GlaxoSmithKline reported that deleting mGluR5, a protein complex that responds to the common brain-signaling molecule glutamate, made mice unresponsive to cocaine. “That finding came out of the blue,” says Worley, who knew mGluR proteins for their interactions with immediate early genes. “I never would have thought this type of protein was linked to dopamine and addiction, because the functions for it that we knew about up to that point were completely unrelated. That’s what scientists love: when you’re pretty sure something is right, but you don’t have a clue why.”
The finding set Worley’s research group on a long search for an explanation. Eventually, in addition to studying the effects of altering genes for the relevant proteins in mice, they partnered with experts in measuring the brain’s electrical signals and in a biophysical technique that detects when chemical bonds are rotated within protein molecules. Using different types of experiments, they pieced together a complex story of how dopamine released in response to cocaine works together with mGluR5 and immediate early genes to switch cells into synapse-strengthening mode.
“The process we identified explains how cocaine exposure can co-opt normal mechanisms of learning to induce addiction,” Worley says. Knowing the details of the mechanism may help researchers identify targets for potential drugs to treat addiction, he adds.
(Image: Milos Jokic)
New mode of cellular communication discovered in the brain
Glial cells send ‘care packages’ including protective proteins and genetic information to nerve cells
Researchers at Johannes Gutenberg University Mainz (JGU) have discovered a new form of communication between different cell types in the brain. Nerve cells interact with neighboring glial cells, which results in a transfer of protein and genetic information. Nerve cells are thus protected against stressful growth conditions. The study undertaken by the Mainz-based cell biologists shows how reciprocal communication between the different cell types contributes to neuronal integrity. Their results have been recently published in the journal PLOS Biology.
Brain function is determined by the communication between electrically excitable neurons and the surrounding glial cells, which perform many tasks in the brain. Oligodendrocytes are a type of glial cell and these form an insulating myelin sheath around the axons of neurons. In addition to providing this protective insulation, oligodendrocytes also help sustain neurons in other ways that are not yet fully understood. If this support becomes unavailable, axons can die off. This is what happens in many forms of myelin disorders, such as multiple sclerosis, and it results in a permanent loss of neuron impulse transmission.
Like other types of cell, oligodendrocytes also secrete small vesicles. In addition to lipids and proteins, these membrane-enclosed transport packages also contain ribonucleic acids, in other words, genetic information. In their study, Carsten Frühbeis, Dominik Fröhlich, and Wen Ping Kuo of the Institute of Molecular Cell Biology at Johannes Gutenberg University Mainz found that oligodendrocytes release nano-vesicles known as ‘exosomes’ in response to neuronal signals. These exosomes are taken up by the neurons and their cargo can then be used for neuronal metabolism. “This works on a kind of ‘delivery on call’ principle,” explained Dr. Eva-Maria Krämer-Albers, who is leading the current study. “We believe that what are being delivered are ‘care packages’ that are sent by the oligodendrocytes to neurons.”
While studying cell cultures, the research group discovered that the release of exosomes is triggered by the neurotransmitter glutamate. By means of labeling them with reporter enzymes, the researchers were able to elegantly demonstrate that the small vesicles are absorbed into the interior of the neurons. “The entire package of substances, including the genetic information, is apparently utilized by the neurons,” said Krämer-Albers. If neurons are subjected to stress, cells that have been aided with ‘care packages’ subsequently recover. “This maintenance contributes to the protection of the neurons and probably also leads to de novo synthesis of proteins,” stated Carsten Frühbeis and Dominik Fröhlich. Among the substances that are present in the exosomes and are channeled to the neurons are, for instance, protective proteins such as heat shock proteins, glycolytic enzymes, and enzymes which counter oxidative stress.
The study has demonstrated that exosomes from oligodendrocytes participate in a previously unknown form of bidirectional cell communication that could play a significant role in the long-term preservation of nerve fibers. “An interaction like this, in which an entire package of substances including genetic information is exchanged between cells of the nervous system, has not previously been observed”, stated Krämer-Albers, summarizing the results. “Exosomes are thus similar to viruses in certain respects, with the major difference that they do not inflict damage on the target cells but are instead beneficial.” In the future, the researchers hope to develop exosomes as possible ‘cure’ packages that could be used in the treatment of nerve disorders.
Researchers Develop Novel Drug That Reverses Loss of Brain Connections in Models of Alzheimer’s
The first experimental drug to boost brain synapses lost in Alzheimer’s disease has been developed by researchers at Sanford-Burnham Medical Research Institute. The drug, called NitroMemantine, combines two FDA-approved medicines to stop the destructive cascade of changes in the brain that destroys the connections between neurons, leading to memory loss and cognitive decline.
The decade-long study, led by Stuart A. Lipton, M.D., Ph.D., professor and director of the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, who is also a practicing clinical neurologist, shows that NitroMemantine can restore synapses, representing the connections between nerve cells (neurons) that have been lost during the progression of Alzheimer’s in the brain. The research findings are described in a paper published June 17 by the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
The focus on a downstream target to treat Alzheimer’s, rather than on amyloid beta plaques and neurofibrillary tangles—approaches which have shown little success—“is very exciting because everyone is now looking for an earlier treatment of the disease,” Lipton said. “These findings actually mean that you might be able to intercede not only early but also a bit later.” And that means that an Alzheimer’s patient may be able to have synaptic connections restored even with plaques and tangles already in his or her brain.
Targeting lost synapses
In their study, conducted in animal models as well as brain cells derived from human stem cells, Lipton and his team mapped the pathway that leads to synaptic damage in Alzheimer’s. They found that amyloid beta peptides, which were once thought to injure synapses directly, actually induce the release of excessive amounts of the neurotransmitter glutamate from brain cells called astrocytes that are located adjacent to the nerve cells.
Normal levels of glutamate promote memory and learning, but excessive levels are harmful. In patients suffering from Alzheimer’s disease, excessive glutamate activates extrasynaptic receptors, designated eNMDA receptors (NMDA stands for N-methyl-D-aspartate), which get hyperactivated and in turn lead to synaptic loss.
How NitroMemantine works
Lipton’s lab had previously discovered how a drug called memantine can be targeted to eNMDA receptors to slow the hyperactivity seen in Alzheimer’s. This patented work contributed to the FDA approval of memantine in 2003 for the treatment of moderate to severe Alzheimer’s disease. However, memantine’s effectiveness has been limited. The reason, the researchers found, was that memantine—a positively charged molecule—is repelled by a similar charge inside diseased neurons; therefore, memantine gets repelled from its intended eNMDA receptor target on the neuronal surface.
In their study, the researchers found that a fragment of the molecule nitroglycerin—a second FDA-approved drug commonly used to treat episodes of chest pain or angina in people with coronary heart disease—could bind to another site that the Lipton group discovered on NMDA receptors. The new drug represents a novel synthesis connecting this fragment of nitroglycerin to memantine, thus representing two FDA-approved drugs connected together. Because memantine rather selectively binds to eNMDA receptors, it also functions to target nitroglycerin to the receptor. Therefore, by combining the two, Lipton’s lab created a new, dual-function drug. The researchers developed 37 derivatives of the combined drug before they found one that worked, Lipton said.
By shutting down hyperactive eNMDA receptors on diseased neurons, NitroMemantine restores synapses between those neurons. “We show in this paper that memantine’s ability to protect synapses is limited,” Lipton said, “but NitroMemantine brings the number of synapses all the way back to normal within a few months of treatment in mouse models of Alzheimer’s disease. In fact, the new drug really starts to work within hours.”
To date, therapies that attack amyloid plaques and neurofibrillary tangles have failed. “It’s quite disappointing because I see really sick patients with dementia. However, I’m now optimistic that NitroMemantine will be effective as we advance to human trials, bringing new hope to both early and later-stage Alzheimer’s patients,” Lipton said.
Neurochemical Traffic Signals May Open New Avenues for the Treatment of Schizophrenia
Researchers at Boston University School of Medicine (BUSM) have uncovered important clues about a biochemical pathway in the brain that may one day expand treatment options for schizophrenia. The study, published online in the journal Molecular Pharmacology, was led by faculty within the department of pharmacology and experimental therapeutics at BUSM.
Patients with schizophrenia suffer from a life-long condition that can produce delusions, disordered thinking, and breaks with reality. A number of treatments are available for schizophrenia, but many patients do not respond to these therapies or experience side effects that limit their use.
This research focused on key components of the brain known as NMDA receptors. These receptors are located on nerve cells in the brain and serve as biochemical gates that allow calcium ions (electrical charges) to enter the cell when a neurotransmitter, such as glutamate, binds to the receptor. Proper activation of these receptors is critical for sensory perception, memory and learning, including the transfer of short-term memory into long-term storage. Patients with schizophrenia have poorly functioning or “hypoactive” NMDA receptors, suggesting the possibility of treatment with drugs that positively affect these receptors. Currently the only way to enhance NMDA receptor function is through the use of agents called agonists that directly bind to the receptor on the outer surface of the cell, opening the gates to calcium ions outside the cell.
In this study, the researchers discovered a novel “non-canonical” pathway in which NMDA receptors residing inside the cell are stimulated by a neuroactive steroid to migrate to the cell surface (a process known as trafficking), thus increasing the number of receptors available for glutamate activation. The researchers treated neural cells from the cerebral cortex with the novel steroid pregnenolone sulfate (PregS) and found that the number of working NMDA receptors on the cell surface increased by 60 to 100 percent within 10 minutes. The exact mechanism by which this occurs is not completely clear, but it appears that PregS increases calcium ions within the cell, which in turn produces a green light signal for more frequent trafficking of NMDA receptors to the cell surface.
Although still in the early stages, further research in this area may be instrumental in the development of treatments not only for schizophrenia, but also for other conditions associated with malfunctioning NMDA receptors, such as age-related decreases in memory and learning ability.