BOSTON, Mass. - Primitive neural cells in the brains of laboratory rats respond to acute brain injuries by moving to the injured area and attempting to form new neurons, according to University of Michigan neurologist Jack M. Parent, M.D. Understanding how this self-repair mechanism works could someday help physicians reduce brain damage caused by strokes or neurodegenerative diseases.
In a presentation here today at the American Association for the Advancement of Science meeting, Jack M. Parent, M.D., an assistant professor of neurology in the U-M Medical School, described results from a series of his experiments with laboratory rats. Prolonged epileptic seizures or strokes in these rats caused neural precursor cells called neuroblasts - cells midway in development between a stem cell and a fully developed neuron - to multiply and form neural chains that migrated across the brain to the site of injury.
"What's fascinating is that neuroblasts responded similarly to both types of brain injury," says Parent. "There's some cue in common that activates their development and growth. We don't know what it is, but we are looking for candidate molecules - growth factors or neurotrophic factors - that stimulate the proliferation and migration of precursor cells."
Parent cautions that, while his results are intriguing, many years of research at the molecular level and in animals will be necessary before human clinical trials could even be considered. "It's not enough to stimulate the development of neuroblasts in human brains and hope they do what you want them to do," Parent says. "There can be harmful consequences."
Until recently, scientists believed the mammalian adult central nervous system - the brain and spinal cord - was incapable of generating new neurons from adult stem cells, a process known as neurogenesis. But now scientists know that precursor cells in a part of the brain called the subventricular zone or SVZ continue to produce new neurons throughout life for a part of the brain called the olfactory bulb, which processes scent. Another area of the brain called the dentate gyrus also generates neuroblasts, which form neurons in the hippocampus -- the section of the brain involved in learning, memory and regulating emotions. "Many other sites in the brain's cortex contain neural progenitor cells, also, but they never develop into neurons," Parent adds.
Prolonged epileptic seizures cause widespread, diffuse damage to neurons in the brain's hippocampus and other parts of the limbic system -- according to Parent, who specializes in epilepsy research. When he examined slices of brain tissue from rats with seizure-induced damage using a special labeling technique that marks rapidly dividing cells, Parent found a significant increase in neuroblast development in the dentate gyrus and the sub-ventricular zone.
"Neuroblasts linked together to form long chains that migrated to the olfactory bulb through tubes formed by astrocytes, or neural structural support cells," Parent says. "We also found neuroblasts outside the olfactory bulb streaming in chains toward the forebrain, but most died before they developed into neurons."
Two weeks after he induced cerebral infarcts or strokes in rats, Parent found a major increase in the number of neuroblasts migrating toward the injury site. Five weeks after the stroke some had developed into neurons. "Most importantly, some of the newborn neurons that migrated to the injured striatum, a motor control area of the brain affected by the stroke, appeared to develop into neurons specific to the striatum," Parent adds.
"Our results show that injury definitely induces proliferation of neuroblasts in the brain. They start to migrate to the injured area and develop into neurons. Some even become neurons appropriate for the injured area," Parent says. "Because the precursor cells move through tubes formed by proliferating astrocytes, it is possible that astrocytes control neurogenesis. More research will be needed to know for sure."
Migration of neuroblasts after injury to the mature brain may not always be beneficial, however. Parent and others have shown that after prolonged seizures, neuroblasts in the dentate gyrus migrate to an area called the dentate hilus where they don't belong. Even though they are in the wrong place, these neuroblasts still appear to develop into dentate granule cells.
"However, they appear to be abnormally hyperexcitable and wire into existing nerve cell networks in a way that may lead to seizures," Parent says. "This suggests that making more new neurons after injury is not always a good thing for brain function."
Despite such obstacles, the idea that the brain can replace nerve cells lost to injury opens up new avenues for potential therapies. Even though the brain's attempt to repair itself is imperfect, Parent believes increased understanding of the process could prove to be important for individuals with brain damage. "You don't have to perfectly rebuild the brain to improve significantly the patient's quality of life after a stroke," he says. "If we could learn how to repair even half the damage, it may be enough."
Parent's research on injury-induced neurogenesis is supported by the National Institute for Neurological Disorders and Stroke (NINDS) of the National Institutes of Health and the Parents Against Childhood Epilepsy (PACE) Foundation.
Feb. 18, 2002
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