All Aboard: Oxygen-carrying protein in the brain could protect against stroke (Stroke)
Authors: Seydel Caroline 
Published: August 2003

Like freight cars carrying precious cargo around the body, hemoglobin travels through the bloodstream in red blood cells, picking up oxygen in the lungs and delivering it to other tissues. Last year, researchers discovered a protein that they dubbed neuroglobin: "neuro" because it is especially abundant in the brain and "globin" because it resembles hemoglobin and related proteins. No one had previously identified a hemoglobinlike protein in the nervous system, and researchers clamored to know what it might be doing. Because neuroglobin binds oxygen, they suspected it might act during stroke, which strikes when brain cells don't get enough blood and subsequently die from lack of oxygen. Perhaps, for example, neuroglobin acts similarly to myoglobin, another related protein, which stores oxygen in muscle cells and releases it when oxygen levels fall; maybe neuroglobin hoards oxygen in brain cells for just such an occasion. Alternatively--or in addition--neuroglobin might thwart the destruction caused by an oxygen shortage by triggering other protective activities. Now researchers studying the molecular basis of stroke reveal that neuroglobin somehow reduces the damage to neurons deprived of oxygen.

Sun and colleagues wondered whether neuroglobin preserves brain cells when oxygen concentrations are low. They probed this idea first by cutting off oxygen to mouse neurons in culture dishes: The amount of neuroglobin in these cells increased about 2.5-fold. To test whether neuroglobin protects the cells under these conditions, they inserted into neurons RNA that binds to and inactivates the single-stranded neuroglobin messenger RNA: This so-called "antisense RNA" zips up the neuroglobin mRNA in the cell and prevents its translation into protein. Then they removed oxygen from the cells' environment. Neuroglobin-deficient cells succumbed much more readily to suffocation than did untreated ones: Only about half as many survived the oxygen deprivation. Finally, the researchers added to neurons a piece of DNA that carries the mouse neuroglobin gene and found that the cells produced twice as much neuroglobin protein as did controls; this supplement improved neuron survival under conditions of oxygen deprivation by about 30%.

Because lack of oxygen causes cell death, the researchers wanted to address whether neuroglobin shields cells only from low oxygen concentrations or also from other insults that spur cell death. Neither too little nor too much neuroglobin affected neurons' responses to deadly toxins such as staurosporine, which stimulates cell suicide, and sodium nitroprusside, which directly blocks oxygen use in the mitochondria, the team reports. These reagents don't interfere with the molecular pathway that fires when cells are deprived of oxygen. Other work further ties neuroglobin to that pathway. Poisons such as cobalt and deferoxamine that mimic oxygen deprivation by activating a gene called
HIF-1
--which turns on when cells start to asphyxiate--step up neuroglobin production. Although these results don't directly reveal whether neuroglobin protects against these noxious agents, the observation suggests that neuroglobin might act in the
HIF-1
pathway, which regulates a number of other genes involved in the response to scant oxygen. Further work is required to establish how neuroglobin exerts its protective effect; researchers speculate that it might maximize the use of the limited oxygen available, or that it turns on the
HIF-1
pathway, which safeguards tissues in a variety of ways, or both.

Because of its possible use to defend against oxygen deprivation, neuroglobin might someday be used to prevent stroke. As a first step toward that goal, Sun and colleagues plan to study mice that lack or overproduce neuroglobin and to compare key characteristics: how long they tolerate insufficient oxygen before suffering from a stroke, for instance, and how much damage the strokes cause. If the therapeutic hope is realized, neuroglobin could wind up carrying good news as well as oxygen.

--Caroline Seydel

Y. Sun, K. Jin, X. O. Mao, Y. Zhu, D. A. Greenberg, Neuroglobin is up-regulated by and protects neurons from hypoxic-ischemic injury.
Proc. Natl. Acad. Sci.
98
, 15306-15311 (2001).
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