Cerebral Palsy
Posted on:January 18, 2012
| Scientists at Washington University School of Medicine, in St. Louis, have shown that a protein may help prevent the kind of brain damage that occurs in babies with cerebral palsy [The Proceedings of the National Academy of Sciences,108 (47): 19054-59].Using a mouse model that mimics the condition in newborns, the researchers found that high levels of the protective protein Nmnat1 substantially reduce damage that develops when the brain is deprived of oxygen and blood flow. The finding offers a potential new strategy for treating cerebral palsy, stroke and perhaps Alzheimer’s, Parkinson’s and other neurodegenerative diseases.
“Under normal circumstances the brain can handle a temporary disruption of either oxygen or blood flow during birth, but when they occur together and for long enough, long-term disability and death can result,” said senior author David Holtzman, MD, head of the Department of Neurology. “If we can use drugs to trigger the same protective pathway as Nmnat1, it may be possible to prevent brain damage that occurs from these conditions as well as from neurodegenerative diseases.” The researchers are not sure how Nmnat1 protects brain cells, but they suspect it blocks the effects of the powerful neurotransmitter glutamate. Brain cells that are damaged or oxygen-starved release glutamate, which can overstimulate and kill neighboring nerve cells. The protective effects of Nmnat1 first were identified five years ago by Jeff Milbrandt, MD, PhD, head of genetics, who showed the protein can prevent damage to peripheral nerves in the extremities of the body. “Cerebral palsy is sometimes attributable to brain injury that stems from inadequate oxygen and blood flow to the brain before, during or soon after birth,” said first author Philip Verghese, PhD, a postdoctoral research associate. “We wanted to see if those injuries still occur in the presence of increased levels of Nmnat1.” The researchers evaluated the effects of oxygen and blood flow deprivation in normal mice and in mice genetically engineered to produce higher-than-normal levels of Nmnat1. As early as six hours later, the mice with enhanced Nmnat1 had markedly less injury to the brain. A week later, when the researchers measured the amount of tissue atrophy in the brain, they found that mice with high Nmnat1 had experienced far less damage to key brain structures like the hippocampus and cortex, which are known to be injured in cerebral palsy. In a series of follow-up studies with collaborators Jeff Neil, MD, PhD, and Yo Sasaki, PhD, the scientists were surprised to see that MRI brain scans showed Nmnat1 might be even more protective than the first experiment suggested. In mice with boosted Nmnat1 levels, the scans revealed little to no brain damage. Laboratory studies of the brain cells indicated that Nmnat1 prevents a particular form of cell death. “There are two types of injury in the developing brain from inadequate oxygen and blood flow,” Dr. Holtzman explained. “One is necrosis, where cells swell rapidly, burst and die. Another is apoptosis, where the cells shrink and die. We found that Nmnat1 prevents necrosis.” Necrosis is believed to be responsible for killing brain cells in ischemic stroke in adults. Dying cells flood the surrounding area with glutamate, which can harm nearby cells. When researchers simulated this process in a test tube, fewer brain cells died in the presence of high Nmnat1. Scientists are following up on several potential explanations for the protective effects of Nmnat1. Dr. Holtzman plans to test the protein in other models of brain injuries and neurodegenerative diseases. The research was supported by the National Institute of Neurological Disorders and Stroke and a grant from Mr. and Mrs. Mark Dehnert through the Goldman Sachs Gives fund. |
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Most treatments for cerebral palsy (CP) are initially directed toward children. What is not clearly established is the long- term effects of such treatments. Many appear helpful in the short term but prove to be disadvantageous in the long run. Selective dorsal rhizotomy (SDR) is a permanent, irreversible neurosurgical procedure for reducing spasticity in cerebral palsy. Parents contemplating SDR for their child would like assurance that that there will not be harmful complications from it as the child ages into adolescence and adulthood. We now have new evidence...
