Apr. 14, 1998 Slice across the human brain, and you'll see tracts of white matter glistening against dull gray matter. The latter contains bodies of nerve cells, which help us fill out tax forms, fall in love and learn the rules of baseball. White matter, on the other hand, contains the long arms or axons of these neurons. The axons cable messages across the brain and down the spinal cord, instructing us to move a pen, kiss a lover or hit a home run.
Stroke and head trauma can rob us of the means to think and act by killing parts of the brain. Studies of how such events damage gray matter have flourished in recent years, and drugs to reduce nerve cell loss now are in clinical trials. But scientists have paid scant attention to loss of white matter, which increases long-term disability, deprives spinal cord patients of bowel and bladder control and can account for most symptoms of multiple sclerosis.
Cells called oligodendrocytes make white matter white. They manufacture myelin, the fatty sheath that insulates axons like plastic around an electrical wire. If their myelin falls into disrepair, axons cease to function, even though they themselves aren't damaged. So protecting oligodendrocytes after brain or spinal cord injury might keep intact axons in action.
A chance observation led researchers at Washington University School of Medicine in St. Louis to discover how oligodendrocytes might die after catastrophes in the central nervous system and how this loss might be prevented. John W. McDonald, M.D., Ph.D., and Mark P. Goldberg, M.D., assistant professors of neurology, and Dennis W. Choi, M.D., Ph.D., the Jones Professor and head of neurology, discovered that oligodendrocytes succumb to elevated levels of a brain chemical called glutamate, an observation that flies in the face of previous dogma. They presented their findings in the March 1998 issue of Nature Medicine.
Co-authors are research assistant Sandy P. Althomsons and research associate Kris Hyrc, Ph.D. The research was performed in the medical school's Center for the Study of Nervous System Injury and funded by the National Institutes of Health and American Paralysis Association.
The researchers also reported that compounds that block glutamate's destructive action reduced stroke-related injury of oligodendrocytes in culture. And McDonald's most recent work has revealed that these compounds, called AMPA receptor antagonists, also protect white matter in the injured spinal cord. The compounds are being examined in clinical trials to evaluate safety, and it soon might be possible to test their effectiveness against central nervous system injury.
"Preserving the function of just a small fraction of the damaged long cables that go down the spinal cord could provide meaningful improvement in day-to-day function for people who sustain spinal cord injury," says McDonald, who also is director of the Spinal Cord Injury Unit at Barnes-Jewish Hospital. In the early 1980s, Washington University in St. Louis researchers discovered that glutamate, a chemical messenger that neurons squirt onto other neurons, turns into a killer when it floods onto neighboring cells from ruptured neurons. They named this phenomenon 'excitotoxicity' because glutamate can overexcite receptors on nearby neurons, opening channels that admit lethal amounts of calcium. These receptors are called NMDA receptors because they can be stimulated in the laboratory with a glutamate mimic called NMDA.
Subsequent experiments convinced the neuroscience community that oligodendrocytes are invulnerable to glutamate damage. First, scientists found that oligodendrocytes do not express NMDA receptors - they have a different type of glutamate receptor, the AMPA receptor, which is not so permeable to calcium. Second, they observed that even high levels of glutamate or AMPA fail to kill oligodendrocytes in culture.
Goldberg and McDonald were culturing different types of non-neuronal cells from mouse brains. They observed that one type of cell, the astrocyte, was not injured by exposure to glutamate or AMPA. To their surprise, however, the cultured oligodendrocytes had functional AMPA receptors and were very vulnerable to the excitotoxic agents. This susceptibility appeared only after the cells were three weeks old, and it was prevented by compounds that stop either AMPA or glutamate from overexciting the receptor.
"So our discovery may have resulted from the fact that our oligodendrocyte cultures were older than those that had been studied previously," Goldberg says. "Or it may have been due to the fact that they were cultured with astrocytes and therefore behaved more like they do in the brain."
To mimic the conditions that follow stroke, Goldberg and McDonald transiently deprived cultured oligodendrocytes of oxygen and glucose. The treatment caused widespread oligodendrocyte death, which again was attenuated by an AMPA antagonist.
Damage to the living brain
To see what happens in the living brain, the researchers injected AMPA into precisely located portions of white matter in rats. An NMDA antagonist also was included. After 24 hours, only 40 percent of the oligodendrocytes in these regions had survived. In contrast, there was little oligodendrocyte death in rats that received only the NMDA antagonist. The same was true for rats that received only NMDA, though this compound killed overlying neurons. The researchers then showed that oligodendrocytes really do express AMPA receptors while they are still in living animals. Recent experiments in which rats suffered traumatic spinal cord injury or stroke have produced the same results.
"The fact that these receptors are expressed and can lead to the death of cells suggests that maybe excitotoxicity of AMPA/kainate receptors is the mechanism of injury in disease states such as head injury and stroke," Goldberg says. "It also may end up being a very important mechanism of white matter injury in the spinal cord," McDonald says. "And white matter injury really is the main determinant of functional outcome in spinal cord patients, at least as far as the ability to walk and retain bowel and bladder control is concerned."
Note: For more information, refer to McDonald JW, Althomsons SP, Hyrc KL, Choi DW, Goldberg MP, "Oligodendrocytes From Forebrain Are Highly Vulnerable to AMPA/kainate Receptor-mediated Excitotoxicity," Nature Medicine 4, 291-297, March 1998.
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