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A Newsletter Exploring Science 
Stroke: The Search for Treatments
Strokes are the third-leading cause of death in the United States behind heart disease and cancer, killing about 275,000 people a year. About 5.4 million stroke survivors live in the United States today, many with significant disabilities. With this great a prevalence, why has it been so difficult to discover drugs to treat this disorder? To understand this, it is important to understand what is a stroke? Basically there are two types of strokes: (1) an ischemic stroke caused by blockage of a blood vessel in the brain, usually by a clot or (2) a hemorrhagic stroke caused by the bursting of a brain blood vessel. The majority of strokes are ischemic (85%) and they have a much better chance of survival than hemorrhagic strokes which are often fatal or lead to significant disability. In either case the result is that there is an interruption of blood flow to an area of the brain, which causes hypoxia (lack of oxygen necessary for cell function). This sets off a series of not well understood events that eventually kills neurons, which are the key cells in the brain. One of the difficulties in stroke research is how different the outcome is, which depends on the length and of the hypoxia, the location of the blood flow interruption, whether the blood vessel reopens, and a variety of other factors. For instance, a small stroke affecting the area of the brain that controls speech can have a devastating effect on the ability of the patient to talk; similarly, if the effect is on the part of the brain controlling motor function the result can be paralysis on one side of the body. On the other hand, many strokes affect parts of the brain not specifically wired to control a function and several months after the stroke a disability may be small or undetectable. The warning signs of a stroke are listed below. These signs are most common in individuals 65 years or older. The "good" news is that there are a variety of strategies to reduce the risk of getting a stroke (listed below) and they generally overlap with the same risk factors for other cardiovascular diseases. Currently there is only one drug approved by the food and drug administration (FDA) for the treatment of stroke - tissue plasminogen activator or TPA. The problem with TPA treatment is that it must be given within three hours of the onset of stroke symptoms or it may actually increase the severity of the stroke. TPA works by dissolving the blood clot. Before it can be administered patients require a brain scan. For this reason TPA can only practically be administered in a hospital under careful supervision. Since the complication risk is very high, many physicians are reluctant to administer TPA fearing a malpractice lawsuit. It is estimated that fewer than two percent of stroke patients receive TPA. Pharmaceutical companies have been attempting to discover drugs that could prevent the brain injury of a stroke for at least twenty years. Most of these are called "neuroprotective" drugs, because they hope to protect neurons from dying, therefore preserving their function. Animal studies have been critical in assisting this research. In both rats and mice models have been developed that either permanently or temporarily block a brain artery. The animals can then be assessed for behavioral changes, and following euthanasia special techniques allow researchers to evaluate brain loss. One surprising fact is that in rodents even significant brain injury leads to only minor deficits; that is, an untrained observer would not be able to distinguish between an animal that received an experimental stroke from a normal animal. A number of novel compounds have shown an ability to both reduce brain injury and improve the minor behavioral deficits in rodents. However, in man these drugs have not been successful in clinical trials with stroke patients. One of the main reasons is that in animals the drug was usually given within one hour of the stroke, while in humans it generally was four to six hours later. Initially, it was thought that because the human brain is so much larger than a rodent brain that it would take longer to become hypoxic; now it appears that the time course of neuronal injury is the same in rodents and man. Because stroke symptoms are often not recognized, it has been difficult to get patients to emergency care rapidly. Therefore, new experimental drugs are being developed that can prevent brain injury even when administered several hours after the stroke. This requires that scientists better understand all the events that lead to neurons dying, so that they can discover drugs that block deadly pathways, but not normal cellular processes. In addition, research is directed towards "neurorestorative" strategies that would help neurons reconnect with each other even weeks after a stroke. This combined with physical therapy may help restore function and lessen disability. Finally, stem cell research may some day allow for the replacement of dead or damaged neurons, which again could help restore function. In conclusion, stroke research has been very challenging with many disappointments. But scientists learn from their mistakes and new drugs and therapies are on the horizon that may help prevent or cure strokes in the future.
STROKE WARNING SIGNS
STROKE RISK FACTORS
High Blood Pressure: INFORMATIVE WEBSITES ON STROKE
http://www.ninds.nih.gov/disorders/stroke/stroke.htm
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