Using a mouse model that mimics the devastating 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 as well as strokes, and perhaps Alzheimer's, Parkinson's and other neurodegenerative diseases. The research is reported online in the Proceedings of the National Academy of Sciences.
"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," says senior author David M. Holtzman, MD, the Andrew and Gretchen Jones Professor and 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 aren't exactly sure how Nmnat1 protects brain cells, but they suspect that 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 were first identified five years ago by Jeff Milbrandt, MD, PhD, the James S. McDonnell Professor and head of genetics at Washington University, who showed the protein can prevent damage to peripheral nerves in the body's extremities. Phillip Verghese, PhD, a postdoctoral research associate in Holtzman's laboratory, wanted to see if the protein's protective effects extend to the brain.
"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," says first author Philip Verghese, PhD, a postdoctoral research associate in Holtzman's laboratory. "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, the Allen P. and Josephine B. Green Professor of Neurology, and Yo Sasaki, PhD, research assistant professor of genetics, the scientists were surprised at what they saw.
MRI scans of the brain showed that 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," Holtzman explains. "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, which temporarily cuts off oxygen and blood flow to the brain. Dying cells flood the surrounding area with a 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 in Milbrandt's and Holtzman's laboratories are following up on several potential explanations for Nmnat1's protective effects. Holtzman plans to test the protein in other models of brain injuries and neurodegenerative diseases.
Verghese PB, Sasaki Y, Donghan Y, Stewart F, Sabar F, Finn MB, Wroge CM, Mennerick S, Neil JJ, MIlbrandt J, Holtzman DM. NAD-synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) protects against acute neurodegeneratoin in developing CNS by inhibiting excitotoxic-necrotic cell death. Proceedings of the National Academy of Sciences, online Oct. 31, 2011.
Michael C. Purdy | EurekAlert!
Individual Receptors Caught at Work
19.10.2017 | Julius-Maximilians-Universität Würzburg
Rapid environmental change makes species more vulnerable to extinction
19.10.2017 | Universität Zürich
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
19.10.2017 | Physics and Astronomy
19.10.2017 | Physics and Astronomy
19.10.2017 | Life Sciences