Feb. 25, 2000 Researchers at Jefferson Medical College have developed an oral vaccine that protects rats’ brains from stroke and prevents seizures. Eventually, such a vaccine may be used for epilepsy and prophylactically for individuals at high risk of stroke.
The oral vaccine causes the body to develop antibodies that recognize a protein in the brain. Because of the brain’s blood-brain barrier, the vaccine causes no impairment of the animals’ behavior, says Matthew During, MD, professor of neurosurgery at Jefferson Medical College of Thomas Jefferson University in Philadelphia, who led the work. "It protects them significantly from subsequent insults such as an epileptic seizure or a stroke for at least five months after a single oral dose."
Dr. During and his colleagues at Jefferson and at the University of Auckland, New Zealand, report their findings February 25 in the journal Science.
Dr. During and his co-workers targeted a specific brain protein, the N-methyl-D-aspartate, or NMDA receptor. NMDA receptors are critical to channel calcium into cells and are associated with brain development, normal signaling and the brain plasticity leading to learning and memory. However, the protein is also involved in the cascade of cellular events leading to brain cell death after brain injury, stroke, severe seizures or other insults.
The vaccine approach entails immunizing the animal and generating antibodies against the NMDA receptor, thus blocking it. "It’s been difficult to develop good drugs because when they get across the blood-brain barrier, they don’t function very well and don’t have much selectivity," Dr. During says. "A major problem in treating many neurological diseases is not so much the target, but those drugs which cross the blood-brain barrier tend to affect and alter the function of all the brain, not just the area where the problem lies.
"Here with our vaccine approach the antibodies don’t get across the barrier efficiently," he says. However, with epilepsy, the increased brain activity allows the antibodies to cross the barrier more readily. "If the antibodies get across the barrier, bind to and antagonize the receptor specifically in the injured brain region, animals will behave perfectly normal and you’ve protected against the epileptic seizure."
The researchers immunized about 100 rats with the anti-NMDA antibody. A month later they gave a subgroup of these animals a neurotoxin, kainate, which caused epileptic-like seizures. The researchers saw "dramatic protection," says Dr. During.
"We studied a variety of control groups and showed that about 70 percent of the rats should have gone into seizures, whereas only 20 percent of the rats immunized against the NMDA receptor did so," he says. "We then asked if this was a nonspecific effect, and studied two further control groups including rats immunized against another brain protein." The scientists showed in the only two animals of nine that developed seizures, one of those animals’ brains was completely normal and protected, "which is unheard of.
"Not only does the vaccine prevent the development of seizures, but if prolonged or repeated seizures were to occur in a rare animal, the brain is protected from this neurotoxic insult," Dr. During says.
In a separate group of animals, a full five months after the vaccination, the scientists induced a stroke by injecting a vasoconstrictor and occluding the middle cerebral artery. "We found dramatic protection in the rats brains, a 70 percent reduction in the volume of the infarct," he says. "It doesn’t stop the stroke from occurring, but the amount of brain damage is diminished by 70 percent."
When the researchers saw how well the vaccine protected the animals’ brains, they subsequently "identified the specific immune response and characterized the antibodies getting to the brain. Our vaccine generated antibodies, which recognized and bound to specific functional regions of the NMDA receptor protein. We also showed that these antibodies penetrated into the brain and their entry was increased in response to an insult."
Finally, Dr. During and his colleagues examined the animals’ behavior. "They were completely normal in terms of motor behavior," he says.
Dr. During’s research group continues to explore experimental vaccines against other devastating diseases such as ALS and Parkinson’s disease, as well as conditions such as depression and pain. "We're trying to broaden it to say, ‘This is a phenomenon that could be taken advantage of in many more diseases in the brain,’" he notes.
The scientists think they may eventually study individuals at high risk for stroke, such as bypass patients, and show, rather than oral vaccination, some sort of "passive immunization – actually give antibodies to this" – can be protective.
"The problem with a vaccine is that because it's such a long term effect, there may be unknown effects that may not be reversible. We will probably just start out giving antibodies for safety reasons," Dr. During says. "We would probably start out giving this to patients during bypass or other surgical procedures when their brains are at risk of stroke. Once we show that works, we can move on to other more severe diseases such as AIDS dementia, and eventually back to people at chronic high risk for stroke, such as those with high blood pressure or carotid stenosis."
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