SCI Forum Reports
SCI Research
February 3, 1998
Bruce R. Ransom, MD, PhD, professor and chair of the UW Department of Neurology, discussed his research into the process by which nerve fibers in the spinal cord are injured. Ultimately, the goal of this line of research is "understanding how to minimize the impact of spinal cord injury," Ransom said.
Nerve cells in the brain and spinal cord are made up of neurons (nerve cell bodies) and long fibers called axons (see figure at right). Axons carry signals to and from the neurons and are covered by a protective sheath called myelin. Axons are metabolically independent from neurons so that if an axon is injured, its function will be disrupted even though the neuron may still be intact.
Like most parts of the brain, the spinal cord is over-designed, Ransom said. "We can get function if as few as one in ten axons survives," he said. "We may have lost some, but if we can get the residual axons to work better, there can be some improvement."
A traumatic injury can tear an axon apart, or, more commonly, it can damage an axon by producing reduced blood flow. Blood supplies the axon with the oxygen and glucose it needs to function. The central nervous system (CNS) requires huge amounts of oxygen and glucose to survive, and this is what makes it so vulnerable, Ransom said. The brain represents only 2% of total body weight but uses 15% of the body's blood flow, 20% of all oxygen intake, and 50% of all glucose intake. "It is an expensive electrical device," Ransom said.
Studies done in the 1940s demonstrated that brain cells stop working 6-8 seconds after their blood supply is cut off. After five minutes, irreversible neuron damage occurs. "So whatever we do in emergency care, we don't have much time," Ransom said. In order to be able to minimize damage, it is important to understand what causes nerve cell damage after the restriction of oxygen and glucose, he said.
The energy used to run the brain's electrical equipment is in the form of adenosine triphosphate (ATP), a chemical generated by the breakdown of glucose. When glucose and oxygen are cut off, ATP production stops, disrupting the orderly balance of ions in the cells. Calcium, normally only present between cells, rushes inside the cells, and activates enzymes that destroy cell membranes and proteins.
Ransom has studied the process of axon death using the optic nerve, a part of the CNS composed of thousands of myelinated axons, in rats. He applied electrical stimulation to one end of an axon and recorded the signal as it was transmitted to the other end. In the absence of oxygen and glucose, axons were unable to carry the signal. But when oxygen was returned to the axons, they gradually recovered, indicating that "we have a little more time" to protect function in the axons than in the nerve cell bodies, Ransom said.
This line of inquiry has shed some light on possible ways to intervene in the process of irreversible axon death, Ransom said. He predicts that in a few years studies will investigate the potential of certain drugs to block the entry of calcium into nerve cells and axons after trauma.
Lowering core body temperature may also play an important role in reducing axon damage because "the metabolic rate of the brain is exquisitely sensitive to temperature," Ransom said. Lowering the temperature of the brain by 1 degree centigrade decreases the brain's metabolism by 7-10%, and a 2-3 degree centigrade drop slows the brain's metabolism by 15-30%. In his animal studies, Ransom found that lowering the temperature of an axon 5 degrees centigrade while witholding oxygen resulted in virtually 100% recovery in axon function after oxygen was restored. In Japan, some medical professionals are attempting to reduce damage after strokes by getting patients to emergency rooms quickly, and rapidly lowering their core body temperatures. "There is abundant evidence that hypothermia is protective," Ransom said.
Ransom took questions from the audience about current research aimed at improving function in people with long-standing SCI. Experimental implants of fetal brain tissue in patients with Parkinson's Disease have so far produced disappointing results, Ransom said. The experimental drug 4-AP (4-amino-pyridine), currently undergoing clinical trials, has been shown to be of some benefit to people with incomplete lesions. The drug changes the physiology of intact but partially demyelinated axons so that electrical signals can flow properly again, thus restoring some function.
Editor's note: Currently, a small trial of 4-AP is being conducted in humans to determine the feasibility of undertaking a large, multi-center clinical trial. The Northwest Regional SCI System expects to participate in such a study, and will seek subjects when that time comes.