Professor Teichberg and his team decided to tackle the problem much like one would water in a sinking ship – and pump the excess glutamate out of the brain.The brain is a sensitive organ. 1.4 million people in the US sustain a traumatic injury to the brain each year, whether in a traffic accident, from a blow to the head or assault, and every 45 seconds, on average, someone suffers a stroke – a blood clot in the brain. Both these conditions – and others such as brain cancer or meningitis – can cause permanent neurological damage.
A Weizmann Institute of Science researcher is developing a drug that, by removing toxic amounts of a chemical produced during the trauma, could drastically reduce damage to the brain.
“My field is neuropharmacology, the influence of drugs on the brain,” explains Professor Vivian Teichberg of the Weizmann Institute’s Department of Neurobiology, a chemist by training, who searches for drug-mediated solutions to brain diseases. His focus is a neurotransmitter called glutamate, a chemical that relays messages between brain cells.
Glutamate plays a vital role in the functioning of the brain, but it also has a dark side: “When you suffer a head trauma or a stroke, the brain reacts in a negative way,” Teichberg told ISRAEL21c. “One of the consequences is the release of glutamate: when a cell dies it releases a large amount of glutamate, which over-excites neighboring cells and kills them.”
This is a chain reaction which leads to the deaths of many more cells than just those directly affected by the head injury or blood clot. In a stroke, for example, the area at risk can be 10 times the size of the core area where the blood clot originated. While the core brain cells can’t be saved, those cells that would be killed by the excess glutamate can be – if reached in time.
Many researchers world-wide have been working on this problem for several decades, trying to develop drugs that block the glutamate from activating receptors on the still healthy brain cells near the site of the injury which would lead to their death. Teichberg decided to take a different approach: “We re-thought the problem and realized that as long as one doesn’t remove the excess glutamate, we won’t achieve anything,” he says. “You have to remove it.”
Teichberg and his team, working together with Prof. Yoram Shapira and Dr Alexander Zlotnik of the Soroka Medical Center and Ben Gurion University of the Negev, decided to tackle the problem much like one would water in a sinking ship – and pump the excess glutamate out of the brain.
“Normally the brain recognizes the fact that the glutamate is extremely toxic and has an inherent defense mechanism which pumps it back into the brain cells,” says Teichberg. However, with trauma or disease, the brain’s normal mechanisms don’t function properly. They need a helping hand. Teichberg’s idea was to move the excess glutamate from the brain into the blood, which would then carry it safely away and prevent its destructive effects.
There is already glutamate in our blood, and so the problem was how to encourage far greater amounts of the chemical to move from the brain into the blood rapidly after brain injury so as to prevent as much cell death as possible. There is an enzyme present in blood, known as GOT, which is able to break down glutamate in the presence of a chemical called oxaloacetate (O). Teichberg figured that by injecting large amounts of O into the bloodstream, this would “drive” more glutamate from the brain into the bloodstream. “After a head injury, you give one injection of O for a short, intense time of thirty minutes, and this drains excess glutamate from the brain into the blood and protects the brain.”
The method has been very successful in rats and a start-up company, Braintact, has been established within the Meytav life science technology incubator in Kiryat Shmona in northern Israel in order to take the research to the next stage: clinical trials on humans.
However, humans don’t have high enough concentrations of GOT in our blood so it is the combination of O and the enzyme GOT that will be injected into the bloodstream in human trials to see if this drives glutamate out of the brain in a similar way and prevents brain damage after a stroke or head injury.
Because brain injuries and conditions are so widespread and there is no current treatment for the problem of toxic glutamate, the US Food and Drug Administration (FDA) is allowing the trials to be “fast-tracked” through the initial processes for the investigation of a potential new drug, says Teichberg, who acts as a consultant to Braintact. He hopes that the first phase of clinical trials will start in four months. If all goes well, and human trials demonstrate the efficacy of this drug, it could be on the market within a decade.
But Professor Teichberg is not resting on his laurels: he is continuing to investigate glutamate and what it does in the blood, which is currently a mystery. He is turning his attention from acute situations such as head trauma and stroke to chronic diseases such as brain cancer, meningitis and the motor neurone disease Amyotrophic Lateral Sclerosis (ALS).
Animal experiments have shown that in rats, brain tumors release glutamate to kill neighboring cells and help the tumor expand. And evidence has been found of too much glutamate in the cerebral-spinal fluid of ALS sufferers, which may be killing their motor neurones. “If we pumped out the excess glutamate this might be able to stop further deterioration,” says Teichberg.
As far as he knows, Teichberg is the only researcher investigating a method for driving excess glutamate from the brain into the blood. But he doesn’t mind being alone in the field. “This has been met with skepticism or ignored completely,” he says. “But if I can save a life, for me that is more important than writing 10 papers [for scientific journals]. We can work at our own pace. That is fine with me.”