An enzyme in the blood might be used to prevent brain damage

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The brain is our most carefully guarded organ, protected by a thick layer of bone and an internal barrier that prevents many substances from getting into brain cells. But when injury does strike – from head trauma, stroke or disease – the consequences can be devastating. This is because a substance called glutamate inundates the surrounding areas, overloading the cells in its path and setting off a chain reaction that damages whole swathes of tissue. Glutamate is always present in the brain, where it carries nerve impulses across the gaps between cells. But when this chemical is released by damaged or dying brain cells, the result is a flood that overexcites nearby cells and kills them.

 

A new method for ridding the brain of excess glutamate – one that takes a completely new approach to the problem – has been developed at the Weizmann Institute of Science. Previous attempts to treat glutamate damage have been based on drugs that must enter the brain in an attempt to prevent glutamate from acting. However, many drugs can’t cross the blood-brain barrier, while other promising treatments have proved ineffective in clinical trials. Prof. Vivian Teichberg of the Institute’s Neurobiology Department, working together with Prof. Yoram Shapira and Dr. Alexander Zlotnik of the Soroka Medical Center and Ben-Gurion University of the Negev, has shown that in rats, an enzyme in the blood can be activated to “mop up” toxic glutamate spills in the brain and prevent much of the damage. This method may soon be entering clinical trials to see if it can do the same for humans.

 

Though the brain has its own means of recycling glutamate, thus keeping this substance in balance, injury causes the system to malfunction, allowing glutamate to build up to dangerous levels. Teichberg reasoned that this problem could be circumvented by passing the glutamate from the fluid surrounding brain cells into the bloodstream. But he first had to have a clear understanding of the existing mechanism for moving glutamate from the brain to the blood. Glutamate concentrations in the blood are several times higher than in the brain, and the body must be able to pump the chemical “upstream,” from an area of low concentration to one of high concentration. Glutamate pumps, called transporters, are found on cells on the outside of blood vessels that come into contact with the brain. Transporters collect glutamate from between brain cells, creating small zones of high concentration that facilitate the release of glutamate into the bloodstream.

 

Basic chemistry told Teichberg that he could affect transporter activity by manipulating the glutamate levels in the blood. When the blood’s glutamate levels are low, the increased difference in concentrations causes the brain to release more glutamate into the bloodstream. Using an enzyme called GOT that is normally present in blood to bind glutamate chemically and inactivate it, he effectively lowered glutamate levels in the blood and kicked transporter activity into high gear. In their experiments, the scientists used this method to scavenge blood glutamate in rats with simulated traumatic brain injury. They found that glutamate was effectively cleared out of the animals’ brains, and damage was prevented.

 

Yeda, the technology transfer arm of the Weizmann Institute, now holds a patent for this method, and a new company based on this patent, called Braintact Ltd., has been set up in Kiryat Shmona in northern Israel. It is currently operating within the framework of Meytav’s Technological Incubator. The USFDA has assured the company of a fast track to approval. If all goes well, clinical trials are planned for the near future.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The method could potentially be used to treat such acute brain insults as head traumas and stroke, and prevent brain and nerve damage from bacterial meningitis or nerve gas. It may also have an impact on such chronic diseases as glaucoma, amyotrophic lateral sclerosis (ALS) and HIV dementia. Teichberg: “Our method may work where others have failed, because rather than temporarily blocking the glutamate’s toxic action with drugs inside the brain, it clears the chemical away from the brain into the blood, where it can’t do any more harm.”    

 

Prof. Vivian Teichberg’s research is supported by the M. D. Moross Institute for Cancer Research; the Nella and Leon Benoziyo Center for Neurosciences; the Carl and Micaela Einhorn-Dominic Brain Research Institute; the Mario Negri Institute for Pharmacological Research - Weizmann Institute of Science Exchange Program; Mr. and Mrs. Irwin Green, Boca Raton, FL; and the estate of Anne Kinston, UK. Prof. Teichberg is the incumbent of the Louis and Florence Katz-Cohen Professorial Chair of Neuropharmacology.

 

 

 

 

 

 

Healthy body - healthy mind” is one of those sayings often quoted to children who resist vegetables or bedtime. But there may be more truth to the saying than your parents ever suspected: A new study reveals a surprising connection between the body’s immune system and the brain.

Though the cells of the immune system patrol the entire body, waging daily battle against all sorts of threats, prevailing wisdom has held that the brain remains neutral territory, blockaded against immune cells and invaders alike - any immune cells straying into the demilitarized zone were believed to interfere with the brain’s activity. But a study by Prof. Michal Schwartz and postdoctoral fellow Dr. Jonathan Kipnis of the Neurobiology Department now challenges this widely held viewpoint, shedding new light on the role of the immune system and its part in maintaining healthy brain function. Their study appeared in the Proceedings of the National Academy of Sciences (PNAS), USA.

Schwartz and Kipnis, who were joined by Dr. Hagit Cohen of Ben-Gurion University of the Negev, tested how mice bred for faulty immune systems performed when challenged to find a hidden platform in a pool of water. While normal mice learned to swim the shortest route in a matter of days, the immunity-challenged mice took much longer. But when the missing immune cells were injected into these mice, their learning curves jumped into the normal range.

Having demonstrated a possible role for immune cells in normal brain functioning, the team asked whether the immune system might also hold the key to mental disorders characterized by imbalanced brain activity. They theorized that the supply of immune cells in the brain in such diseases is either insufficient or subject to malfunction. If so, an immune system boost might be enough to overcome the impairment.

For this experiment, the scientists gave normal mice an amphetamine drug that mimics the effects of mental dysfunction in the brain. They then administered the drug Cop-1, which appears to act as a broad vaccine for the whole immune system. The group that did not receive Cop-1 vaccination exhibited disturbed, irrational behavior during the learning test, whereas the vaccinated mice behaved much like normal ones, learning to swim for the platform without any symptoms of mental dysfunction.

“There’s a seemingly logical connection,” says Schwartz. “Age- and AIDS-related dementias, for instance, might be tied to the decline in immune function. Our most important finding is that the brain does not operate independently of the rest of the body’s systems; rather, the immune system plays a pivotal role in its performance.”

Because the study impacts on several areas of higher brain function, including learning, emotions and mental stability, it might have important implications for different fields of neuromedical research. Further studies based on these findings may one day yield vaccines to prevent or treat such diseases as schizophrenia, post-traumatic stress disorder and dementias.

The dopamine tightrope walk

Immunity is a tricky balancing act. Too much, and autoimmune diseases such as diabetes or multiple sclerosis can result. Too little, however, has been shown to be tied to tumor growth and nervous system degeneration. To ensure that the autoimmune T cells will help without hurting, a second set of cells, called regulatory T cells (T-reg), work to keep them in check.

But what regulates the regulators? For some time, scientists have searched for an answer. Schwartz, Kipnis and members of their lab team have now proposed that the key to immune control may lie in the brain. In recently published research, they showed that dopamine - a pivotal chemical messenger more commonly known to be involved in movement, feelings and emotions - provides a direct line of communication to the regulators. It controls T-reg cell activity, ultimately allowing the autoimmune T cells to function upon need without the risk of developing autoimmune disease.

Indeed, research by others has provided tantalizing hints that dopamine imbalances may affect immunity: high dopamine levels have been linked to reduced tumor and neurodegenerative conditions, whereas dopamine deficiency increases the rates of these diseases, while reducing autoimmune pathologies.

Prof. Schwartz’s research is supported by the Nella and Leon Benoziyo Center for Neurosciences; the Alan T. Brown Foundation to Cure Paralysis; the Carl and Micaela Einhorn-Dominic Brain Research Institute; the Glaucoma Research Foundation; the Daniel Heumann Fund for Spinal Cord Research; Mr. and Mrs. Irwin Green, Boca Raton, FL; and Mr. and Mrs. Richard D. Siegal, New York, NY. She is the incumbent of the Maurice and Ilse Katz Professorial Chair of Neuroimmunolgy.

While some people try to remember, others try unsuccessfully to forget. People whose memories have a debilitating effect, such as trauma sufferers who remain haunted by their experience throughout their lives, would benefit from the ability to intentionally dim or erase specific memories without affecting the others.

A step toward reaching this goal has recently been made by a Weizmann team. The scientists have uncovered a fundamental rule governing the workings of the brain. The findings were recently published in Science.

Every memory that we acquire undergoes a "ripening" process (called "consolidation"), which lasts a few hours after the memory is formed. During this time, certain treatments can erase that memory. Until recently, the accepted belief was that every memory consolidates just once, and after that the window of opportunity for erasing that memory closes.

However, recent evidence has shown that calling up a memory might again make it susceptible to disruption. If true, it might be possible to activate a "memory eraser" immediately after the act of remembering, even though years may have passed since the original memory was formed.

Yet leading labs in the world, spurred on by that evidence, came up with seemingly contradictory results: Working with animals, they found that only in some cases did it appear possible to erase old memories upon recall.

The current findings, made by Prof. Yadin Dudai of the Neurobiology Department, explain the puzzling discrepancies in the previous findings and shed light on how memories are recalled and stabilized.

Winner loses all

To understand the findings, think of the bits of information stored in our memories. Each may have many associations, some conflicting with others. For instance, a certain food can arouse memories of taste -  delicious or disagreeable; a person can be remembered in pleasant or unpleasant contexts, and so on. When we next taste the food or see the person, all of the associated memories are evoked. But in the end, only one of them will determine our reaction (i.e., become dominant). This memory dictates whether we will eat the food or reject it, whether we will smile at our acquaintance or ignore him. Dudai's team, which included Mark Eisenberg, Tali Kobilo and Diego Berman, found that only the memory that won the competition for dominance became sensitive to erasure. It is this memory that must be consolidated once again before being reinstalled in long-term memory. In other words, the winner, under the appropriate circumstances, loses all. In Dudai's words, "The stability of the recalled memory is inversely correlated with its dominance."

Dudai's team carried out the study with rats and fish. The rats learned to remember flavors; the fish learned to remember flashes of light. In both instances, the animals were trained to associate the stimuli with conflicting memories (the light, for instance, would signal danger only some of the time). In both species, researchers showed that the dominant memory was the only one that could be erased by administering an appropriate drug within a few minutes of recall.

Studies on humans have not yet been conducted, but Dudai points out that the closer we get to the basic principles of memory, the more similarities exist among animals, including humans. Thus drugs found to be effective in eliminating memories in animals may work in humans as well, offering a much awaited piece of good news to trauma sufferers.

DEFINING MEMORY

Dudai's recently published book, Memory from A to Z, provides a unique and valuable introduction to the field of memory for students and researchers alike. It consists of over 130 entries, bound within a coherent conceptual framework. Each entry starts with a definition, or set of definitions, followed by an in-depth and provocative discussion of the origin, meaning, usage and applicability of ideas and problems central to the science of memory and scientific culture at large. The entries provide a versatile tool kit as a source of definitions, information and further reading, as well as a trigger for contemplation, discussion and experimentation. The book can serve as a useful aid to study, teaching and debates, as well as a trigger for future experimentation.

Prof. Dudai's research was supported over the years by the Abe and Kathryn Selsky Foundation; the Nella and Leon Benoziyo Center for Neurosciences; the Lester Crown Brain Research Fund; the Abramson Family Brain Research Program; the Carl and Michaela Einhorn-Dominic Brain Research Institute; and the Murray H. & Meyer Grodetsky Center for Research of Higher Brain Functions. He is the incumbent of the Sara and Michael Sela Professorial Chair of Neurobiology.