Scientists are on the brink of doing the unthinkable-replenishing the brains of people who have suffered strokes or head injuries to make them whole again. If that is not astonishing enough, they think they may be able to reverse paralysis. The door is at last open to lifting the terrifying sentence these disorders still decree-loss of physical function, cognitive skills, memory, and personality.
Until recently there was virtually nothing doctors could do for the 500,000 Americans who have strokes each year, the 500,000 to 750,000 who experience severe head injury, or the 10,000 people who are paralyzed after spinal cord damage (3). However, that is about to change. Researchers now think it may be possible to replace destroyed brain cells with new ones to give victims of stroke and brain injury a chance to relearn how to control their body, form new thinking processes, and regain emotions. After demolishing the long-standing myth that brain cells cannot regenerate or proliferate, scientists are developing ways to stimulate cells to do just that. Although stroke, head injury, and paralysis are three of the most devastating things that can happen to anyone, scientists have recently learned that the damage they cause is not preordained. It takes place over minutes, hours, and days, giving them a precious opportunity to develop treatments to halt much of the damage. Most of the new remedies are not yet available, but an explosion of research in the last five to ten years has convinced scientists that some of them will work (8).
Guided by fabulous results in preventing permanent damage from stroke and other injuries to the central nervous system in rats and other animals, researchers around the world have launched scores of trials in humans (12). However, many promising new therapies are sitting on the shelf because of a lack of money and other resources necessary to conduct large, lengthy, and expensive studies to conclusively show that a new drug or treatment really works in people. The requirement for safety and efficacy can be frustrating, especially for badly needed treatments that are very promising, but such caution is necessary.
One organization is trying to raise funds for a major study to test a pill for paralysis-4 amino pyridine (4 AP) -which has shown promising results in preliminary human trials (14). About half of the small number of people in the study, who had been paralyzed for four to fifteen years, regained some sensation and muscle function when they were given intravenous infusions of 4 AP. In the new study the drug will be taken in pill form. The benefit lasted for days in some people. Although the effect gradually faded, doctors and patients have been amazed.
A similar story is unfolding in traumatic head injury. Preliminary results from early studies have shown that using cooling blankets to lower temperatures four to five degrees improves recovery by 15 to 16% (8). As promising as the small studies are, they are not convincing enough to mandate all emergency rooms to cool head-injury patients who are comatose. A major study is needed to prove that it really works and that it should become standard care. After years of wondering about whether cooling a patient could dramatically reduce the damage from head trauma, the National Institutes of Health has decided to fund major nine-center study (3).
Scientists are finding that treatments that work in one type of injury-stroke, head trauma, or spinal damage-are likely to work in the others. All of these disorders share many of the same mechanisms of cell destruction, which come in two phases, primary and secondary injury. In the primary, or initial injury, blood flow to a part of the brain is blocked by a clot that plugs an artery or by a physical blow. Brain cells, or neurons, are either damaged or die right away because they are deprived of nourishing blood. This initial destruction then triggers a chemical attack against tissue that was not damaged in the primary injury. The second phase of injury invokes a process called excitotoxicity and it affects nearby healthy cells, often killing more brain tissue than the initial injury (10). Like someone yelling "fire" in a crowded theater, damaged and dying cells scream out a slew of chemicals. These chemicals, which normally help brain cells talk to each other, become dangerously toxic in excessive amounts. They literally cause healthy cells to become overexcited to the point of death, when they too spew out their deathly chemicals.
Interestingly, scientists believe that excitotoxicity is a genetically programmed suicide mechanism devised by nature to kill unneeded or unhealthy cells. Such cell death occurs during fetal development, for instance, to get rid of billions of overproduced brain cells and the webbing between fingers (10). It is this excitotoxic response that is rapidly triggered in stroke, head trauma, or spinal injury to produce the destructive secondary injury. Evidence also indicates that the excitotoxic reaction can occur over a longer period of time, causing a slow form of suicide that may be the final pathway for cellular death in Alzheimer's, Parkinson's, and other degenerative neurological disorders.
The suicide reaction, its scientific name is apoptosis, begins when a damaged or dying neuron releases massive amounts of neurotransmitter called glutamate (1). Glutamate is normally one of the most important chemical messengers in the brain. Nonetheless, when too much glutamate is present, the NMDA receptors, which act as "doors" on cell surfaces, are jammed open (13). Sodium floods in, causing the cell to swell. Calcium rushes in and smashes at the cell's genetic controls, producing enzymes that eat away the cell's internal support structure and destructive molecules, called free radicals, that chew away its membrane wall. The discovery of the key steps in the suicide cascade of secondary injury is leading to the development of drugs to block them. Experiments in animals show that by blocking the secondary injury, much of the damage that normally occurs from a stroke, head trauma, or spinal injury can be prevented.
Two drugs that block the NMDA receptor, thereby preventing glutamate from entering a cell and starting the suicide reaction, have been found to be 40 to 70% effective in preventing brain damage from stroke in animals (10). The drugs, cerestat and selfotel, are in clinical trials with people who have had strokes or severe head injuries (2)(11). Another drug has been designed to prevent damaged neurons from releasing glutamate and still others are intended to block sodium (lubeluzole) and calcium (nimodapine) from flooding into healthy cells (9). Tirilazad, which neutralizes cell-damaging free radicals, has been approved for use in male stroke victims in five European countries after successful clinical trials there (5). The drug was only marginally effective in women, perhaps because females eliminate the drug too swiftly from their bodies. Trials using higher doses for both men and women are under way in the United States.
Scientists are also trying to disarm the enzymes that chomp away at the inside of neurons. A drug that dramatically blocks enzymatic destruction of cells in animal models of brain injury has been developed. As good as some of these new drugs are, they are even better when used in combination. Animal studies have shown that combining two or more of the promising drugs that block secondary injury, or mixing them with clot-busting medication called TPA or with whole body cooling, produces better results than when each is used alone (6). Cooling slows cellular function, thereby preventing the production of dangerous levels of glutamate, which starts the secondary injury response.
How quickly that threshold is being crossed was demonstrated recently by the startling results of a study showing that TPA can dramatically reduce brain damage from stroke, the main cause of adult disability and the third leading cause of death in the United States. The study is a major breakthrough, providing hope where there was none. Receiving TPA within three hours of a stroke increased by 55% the chances that a patient would recover with little or no brain damage (6). The window of opportunity is important because giving TPA after three hours could cause dangerous bleeding in the brain. TPA may be effective in 50% of more of the patients whose strokes are caused by clots. Giving TPA to patients who have suffered bleeding strokes from torn vessels would be dangerous because it could increase the risk of more bleeding. Physicians use CAT scans, which provide images of the brain, to determine which type of stroke has occurred.
The turning point in brain-injury research came in 1990 when a team of researchers reported that a drug called methylprednisolone could significantly reduce paralysis from spinal cord injury (7). The study sent shock waves through the medical world, shattering the firmly held belief that nothing could be done to save injured neurons. When given to patients within six hours of a spinal injury, methylprednisolone increased recovery of function by 20%. The drug acts as both a powerful antioxidant and an anti-inflammatory agent.
The care of people with spinal cord injuries has changed quickly. Before 1990, when it was thought there was absolutely nothing that could be done for these patients, medical personnel did not hurry to treat them. These patients would often lie in emergency rooms for hours until a neurosurgeon could be found to see them. Now, people with spinal cord injuries are treated as rapidly as are people with heart attacks. Paramedics are equipped with spine boards to stabilize patients and prevent further injury. They are given methylprednisolone immediately. The use of methylprednisolone has dramatically improved the outcome of spinal cord injuries. Before 1990, 67% of patients with spinal trauma had no sensation or movement below the point of injury. Today, the figure has been reduced to 37%; thousands of patients are recovering more function and are able to take care of themselves (4).
Tremendous leaps and bounds have been made from that time not long ago when the scientific community thought nothing was possible. The key to all of this is the issue that the majority of scientists now believe that the central nervous system can regenerate. They are now convinced that it is only a matter of time before it discovered how to make it grow. The unthinkable is now conceivable.
(2) CAMBRIDGE NEUROSCIENCE REPORTS PRELIMINARY ANALYSIS OF CERESTAT
(3) HealthLink Home Health: Paralysis and Spinal Cord Injury
(4) Long-Term Methylprednisolone Improves Recovery From Spinal Cord Injury
(5) Mbox: RE: Spinal Cord Injury-Sygen GM-1 & Tirilazad
(6) Mental Health Net - Strokes
(7) Methylprednisolone Improves Recovery in Spinal Cord Patients
(9) New drug may offer effective therapy for stroke patients
(10) Secondary Excitotoxicity
(12) Spinal cord injuries and stroke victims: new medications to slow down
(13) STABLE CEREBELLAR CELL LINES EXHIBITING SUSCEPTIBILITY TO GLUTAMATE TOXICITY. Technology Licensing Opportunity.
(14) WoMS - NZ Medical Bulletin
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This paper reflects the research and thoughts of a student at the time the paper was written for a course at Bryn Mawr College. Like other materials on Serendip, it is not intended to be "authoritative" but rather to help others further develop their own explorations. Web links were active as of the time the paper was posted but are not updated.