Hope for Stroke Victims; Turning Off Stress; Paper Archives Reveal Pollution’s History

Hope for Stroke Victims

Two new studies support a novel approach based on Weizmann Institute scientists’ research

Much of the devastation of stroke and head trauma is due to damage caused by the overproduction of a substance in the brain called glutamate. Preventing this damage has been impossible, until now, as many drugs don’t cross the blood-brain barrier, and those that do often don’t work as intended. But a method originally devised at the Weizmann Institute of Science may, in the future, offer a way to avert such glutamate-induced harm.

Prof. Vivian I. Teichberg of the Institute’s Department of Neurobiology first demonstrated a possible way around these problems in 2003. Glutamate — a short-lived neurotransmitter — is normally all but absent in brain fluids.  After a stroke or injury, however, the glutamate levels in brain fluid become a flood that overexcites the cells in its path and kills them. Instead of attempting to get drugs into the brain, Prof. Teichberg had the idea that one might be able to transport glutamate from the brain to the blood using the tiny “pumps,” or transporters, on the capillaries that work on differences in glutamate concentration between the two sides. Decreasing glutamate levels in blood would create a stronger impetus to pump the substance out of the brain. He thought that a naturally occurring enzyme called glutamate-oxaloacetate transaminase (GOT) could “scavenge” blood glutamate, significantly lowering its levels. By 2007, Prof. Teichberg and his colleagues had provided clear evidence of the very strong brain neuroprotection that oxoloacetate (a chemical similar to GOT) afforded rats exposed to a head trauma.

Two new studies — conducted by Francisco Campos and others from the lab of Prof. Jose Castillo in theUniversity of Santiago de Compostela, Spain — now provide a definitive demonstration of Prof. Teichberg’s results. In the first, the scientists conclusively showed that oxoloacetate injected into rats with stroke-like brain injuries reduces glutamate levels both in the blood and in the affected brain region, while significantly lessening both cell death and the swelling that can accompany stroke. In the second, a team of neurologists in two different hospitals checked the levels of glutamate and GOT in several hundred stroke victims who were admitted to their hospitals. They found that the most significant predictor of the prognosis — how well the patients would recover at three months and how much brain damage they would suffer — was the levels of these two substances. High glutamate levels correlated with a poor outcome, high GOT levels with a better one.

The overall implication of these two papers is that administering GOT might improve a patient’s chances of recovering, as well as speeding up the process. In addition to stroke and head trauma, a number of diseases are characterized by an accumulation of glutamate in the brain, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy, glaucoma, certain brain tumors, and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), and there is hope that, in the future, treatments to scavenge glutamate could relieve the symptoms and improve the outcomes for a number of neurological problems. Yeda, the technology transfer arm of the Weizmann Institute, holds a patent for this method.

Prof. Vivian I. Teichberg’s research is supported by the Nella and Leon Benoziyo Center for Neurosciences; the Carl and Micaela Einhorn-Dominic Brain Research Institute; and the Legacy Heritage Fund Program of the Israel Science Foundation. Prof. Teichberg is the incumbent of the Louis and Florence Katz-Cohen Professorial Chair of Neuropharmacology.

Turning Off Stress

Post-traumatic stress disorder (PTSD) can affect soldiers after combat or ordinary people who have undergone harrowing experiences. Of course, feelings of anxiety are normal and even desirable — they are part of what helps us survive in a world of real threats. But no less crucial is the return to normal — the slowing of the heartbeat and relaxation of tension — after the threat has passed. People who have a hard time “turning off” their stress response are candidates for PTSD, as well as anorexia, anxiety disorders, and depression.

How does the body recover from responding to shock or acute stress? This question is at the heart of research conducted by Dr. Alon Chen of the Institute’s Department of Neurobiology. The response to stress begins in the brain, and Dr. Chen concentrates on a family of proteins that plays a prominent role in regulating this mechanism. One protein in the family — CRF — is known to initiate a chain of events that occurs when we cope with pressure, and scientists have hypothesized that other members of the family are involved in shutting down that chain. In research that appeared in the Proceedings of the National Academy of Sciences (PNAS), Dr. Chen and his team have now, for the first time, provided sound evidence that three family members — known as urocortin 1, 2, and 3 — are responsible for turning off the stress response.

The research group, including Adi Neufeld Cohen, Dr. Michael Tsoory, Dmitriy Getselter, and Shosh Gil, created genetically engineered mice that don’t produce the three urocortin proteins. Before they were exposed to stress, these mice acted just like the control mice, showing no unusual anxiety. When the scientists stressed the mice, both groups reacted in the same way, showing clear signs of distress. Differences between the groups only appeared when they were checked 24 hours after the stressful episode: While the control mice had returned to their normal behavior, appearing to have recovered completely from the shock, the engineered mice were still showing the same levels of anxiety the scientists had observed immediately following their exposure to the stress.

Clearly, the urocortin proteins are crucial for returning to normal, but how, exactly, do they do this? To identify the mechanism for the proteins’ activity, Dr. Chen and his team tested both groups of mice for expression levels of a number of genes known to be involved in the stress response. They found that gene expression levels remained constant during and after stress in the engineered mice, whereas patterns of gene expression in the control mice had changed quite a bit 24 hours after the fact. In other words, without the urocortin system, the “return to normal” program couldn’t be activated.

Says Dr. Chen: “Our findings imply that the urocortin system plays a central role in regulating stress responses, and this may have implications for such diseases as anxiety disorders, depression, and anorexia. The genetically engineered mice we created could be effective research models for these diseases.”

Dr. Alon Chen’s research is supported by the Nella and Leon Benoziyo Center for Neurosciences; the Nella and Leon Benoziyo Center for Neurological Diseases; the Carl and Micaela Einhorn-Dominic Brain Research Institute; the Irwin Green Alzheimer’s Research Fund; Mark Besen and the Pratt Foundation, Australia; Roberto and Renata Ruhman, Brazil; and Martine Turcotte, Canada. Dr. Chen is the incumbent of the Philip Harris and Gerald Ronson Career Development Chair.

Paper Archives Reveal Pollution’s History

Some of the history preserved in old tomes and newspapers may be hiding between the lines of print. A Weizmann Institute scientist has found that the paper in such collections contains a record of atmospheric conditions at the time the trees that went into making it were growing. By analyzing the carbon isotopes in bits of paper clipped from old magazines, Prof. Dan Yakir of the Department of Environmental Sciences and Energy Research in the Faculty of Chemistry has traced the rising effects of atmospheric pollution from burning fossil fuel going back to beginnings of the Industrial Revolution.

Scientists generally reconstruct the record of past climate change from such sources as ice cores or tree rings. But a reliable tree ring history, says Prof. Yakir, requires an analysis of quite a few trees. “Rather than going to forests all over the world to sample trees,” says Prof. Yakir, “we went to the local library.” In the Weizmann library’s archives, Prof. Yakir found issues of the scientific journals Science, Nature, and the Journal of the Royal Chemical Society going back over 100 years to the late 19th century.  Removing small samples from the margins of successive volumes, he took them back to the lab for analysis.

The analysis was based on a finding that the proportion of a carbon isotope — carbon 13 (13C) — to its lighter counterpart — carbon 12 (12C) — could provide information on the carbon dioxide, or CO2, added to the atmosphere from burning fossil fuel. This is based on a cycle that begins with plants taking up CO2 in photosynthesis. All plants prefer to use CO2 made with the more common version of carbon, 12C, than the slightly heavier 13C.  Plant biomass from millions of years ago was transformed into reservoirs of oil, gas, and coal, and so these are naturally low in 13C, as well. When we started to burn those reservoirs following the Industrial Revolution, we began returning the 13C-poor CO2 to the atmosphere. Now the atmospheric 13C content has become increasingly diluted, and this is reflected in the carbon ratios in the trees milled for pulp and paper. Prof. Yakir’s work shows that this continuing dilution is, indeed, clearly recorded in the archival paper and, plotted over time, it demonstrates the increasing intensity of our fossil fuel burning in the past 150 years.

This project has been ongoing for about 14 years, with figures from new issues added over time. In the process, says Prof. Yakir, he has had to learn something about the paper industry. Some early issues, for instance, had been printed on rag paper (made of cotton, flax, etc.) rather than wood pulp, while blips in the data around the time of WWII led Prof. Yakir to suspect that the paper was either recycled, or again supplemented with rag content to make up for wartime shortages.

Anomalies aside, 13C levels in the paper, especially for two of the journals, were a good match for existing atmospheric records, and even revealed some local phenomena, including differences between American and European records. In addition to alerting climate scientists to a very well organized, untapped source of global change records, says Prof. Yakir, the technique could be used to authenticate antique paper samples.

Prof. Dan Yakir's research is supported by the Cathy Wills and Robert Lewis Program in Environmental Science and the estate of Sanford Kaplan.