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2000 First Web Report
This semester we learned about the paralysis of Christopher Reeves. In thinking about his condition, I began to wonder where researchers stood in their attempt to cure paralysis. Paralysis was often considered to be completely irreversible. However, I found that the last ten years have brought huge advances in our understanding of the nervous system and spinal cord injury. Even though paralysis due to spinal cord injury is still, for the most part, permanent, several drugs and techniques show promise in reversing the effects of paralysis.
In order to understand the difficulties of curing paralysis, we must first understand the nature of spinal cord injury. When the spinal cord is injured due to trauma, there is localized death of the nerve cells. (1) The initial injury is only the beginning of the cell death. In the hours, days, and weeks following the injury, nerve cells continue to die above and below the original wound. When the area begins to heal, scar tissue, fluid-filled cysts, and cavities occupy an area where the tissue was once healthy. (4) Many of the nerve fibers at the injured area actually separate into two pieces. The part of the fiber that is torn from the soma dies within 48-72 hours. This part does not regenerate, and cell/cell communication is lost below this point. Some cells, on the other hand, remain intact, but lose their myelin. Myelin is a fatty substance that is necessary to conduct electrical signals along the axon. "[It] increases the speed of transmission of signals from one nerve cell to the next, and without myelin the signal may deteriorate so much that it does not reach its target at all." (2) It is entirely possible that the nerve cells and their axons may survive the trauma, but paralysis still occurs because of the destruction of the myelin sheath. In order to reverse the effects of the spinal cord injury, the patient must receive treatment depending on which damage category their injury falls into.
Methylprednisolone is the first drug which was proven to control spinal cord damage in humans. It is unclear exactly how methylprednisolone works, but it is thought to reduce inflammation, the release of glutamate, and the accumulation of free radicals. Immediately after trauma to the spinal cord, tiny hemorrhages appear due to blood vessel damage. The resultant swelling inhibits the delivery of nutrients and oxygen to the nerve cells, causing them to die. At the same time, the damaged nerve cells and their axons begin releasing toxic chemicals, one of which triggers a process known as excitotoxicity. In a normal spinal cord, the ends of many axons secrete a tiny amount of a chemical called glutamate. When glutamate binds to the receptors of neurons, it causes them to send electrical pulses. When spinal neurons and axons are damaged, however, they release large quantities of glutamate. The high amount of glutamate causes the neighboring neurons to open their channels to excessive amounts of ions, which react to form free radicals- highly reactive substances that can destroy previously healthy neurons. Methylprednisolone inhibits the release of glutamate, which controls the amount of destructive free radicals that form. This helps to localize the injury, and prevent the nerve tissue death from spreading.
If the injury is due to demyelination, it is possible to graft Schwann cells into the brain to myelinate central axons. Schwann cells are glial cells that form myelin sheaths in the peripheral nerves. When they are grafted into the brain, they can initiate remyelination and possibly restore function. (2)
The drug 4-aminopyridine (4 AP) can also overcome the effects of demyelination. In an experiment, behavioral improvements could be seen in paraplegic dogs in as little as 15 minutes after the injection. In the initial human trials, 4 AP was shown to have a slightly beneficial effect in many patients. The best feature of 4 AP is that it can produce effects even years after the injury.
If the paralysis is due to the separation of nerve fibers, it is possible to direct the growth of normal and injured fibers by applying a weak electrical field. In an experiment at Purdue Center for Paralysis Research, scientists produced a weak electrical current across a spinal cord injury in naturally paralyzed dogs. This procedure, called Oscillating Field Stimulation (OFS), involves applying an electrical field in which the polarity is reversed every 15 minutes. The paraplegic dogs who received the OFS treatment showed greater signs of recovery from severe spinal cord injury than dogs who did not receive the treatment. The dogs had to be treated within 18 days of the onset of the paraplegia. OFS would not be effective weeks or years after the injury. The dogs were evaluated immediately before and after the surgery, after 6 weeks, and after 6 months. After six months, the combined neurologic score of the dogs treated with the OFS was significantly better than that of the control dogs. (1)
Another promising treatment of paralysis due to the separation of nerve fibers is the fusion and repair of neurons using polyethylene glycol (PEG). Scientists applied this hydrophilic polymer to the severed spinal cord of guinea pig for two minutes, then removed it. They found that when they fused the cut nerve cells of guinea pigs using PEG, the restored spinal cords would transmit between five and 58 percent of the pre-trauma impulses. PEG literally fused together the membrane of the separated axon. (3) In another experiment, PEG was applied to a spinal cord following a compression injury. The loss of nerve impulse conduction was immediately reversed in the animals treated with PEG, and the animals treated with the placebo continued to experience the absence of nerve impulse conduction.
Neurotransplantation is a technique used to attempt to replace nerve cells that were killed by an injury. Since mature nerve cells cannot replicate, scientists are trying to replace the dead nerve cells with grafted nerve cells in hopes that the new cells would develop into the nervous system. Adult nerve cells are unlikely to transplant successfully, but fetal nerve cells have been transplanted quite successfully in laboratory animals. Because of the ethical issues raised by using human fetal tissue, scientists are also researching the use of stem cells. These are unspecialized cells in the nervous system that can replicate and develop into nerve and glial cells. In theory, the stem cells could be transplanted into the spinal cord to form new neurons and their glia. If scientists can one day perfect this technique in humans, new neurons could replace the dead scar tissue that results from a spinal cord injury. (4)
In the past ten years, scientists have made huge advances in the study of spinal cord injuries. They have developed a drug to help prevent the spread of nerve cell death. Several techniques have been developed to remyelinate injured nerve cells and to bridge the gap between separated axons. Eventually, neurotransplantation will become a feasible option for patients with spinal cord injuries, and the once absurd notion of reversing paralysis will become a reality.
1)www.vet.purdue.edu/cpr/research.html">Purdue Center for Paralysis Research
2)www.miamiproject.miami.edu/miami-project/basic.htm ">The Miami Project to Cure Paralysis
3)www.spinalinjury.net/html/body_stimulation.html">Spinal Cord Injury Resource Center
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