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Weill Cornell team discovers how brain's own tPA helps regulate blood flow to neurons
Date:1/17/2008

was the finding from recent studies that tPA somehow modulates the activity of a protein lying on the surface of neurons called the NMDA receptor," Dr. Iadecola explains. "This receptor serves as a gateway of communication between adjoining neurons, with glutamate being the 'currency' of exchange. Fluctuating levels of tPA seemed to influence just how much of that currency got through as brain cells became more or less active."

Exploring this mechanism further, Dr. Iadecola's team utilized a genetically engineered "knockout" mouse that lacked neuronal tPA. They tweaked the mouse's whiskers and watched blood flow in the area of the rodent's brain linked to whisker sensitivity.

"In the knockout mouse, blood flow in that area did not change as much upon whisker stimulation -- confirming that tPA is necessary to boosting local blood flow," Dr. Iadecola says.

But how was tPA working, exactly? The prevailing theory -- that the enzyme impacted directly on the NMDA receptor -- was quickly proven wrong. "We found that tPA was not acting as any kind of direct 'choke' on the NMDA receptor to allow more or less glutamate into the cell," says Eduardo Gallo, a graduate student in the Department of Neurology and Neuroscience, who played a key role in the study.

So, the team looked elsewhere at other rate-limiting mechanisms that might explain tPA's effects.

"One of the end-products of NMDA receptor activity is nitric oxide (NO), a powerful vasodilator," Gallo notes. "In our experiments, we discovered that tPA helps control how much NO can be made by activation of the NMDA receptor. TPA does so by boosting the ability of neuronal nitric oxide synthase (nNOS) -- an enzyme -- to produce NO. More tPA means more active nitric oxide synthase -- and more of this enzyme means more vessel-widening NO. The end result: a localized boost in blood flow to brain cells."

Questions remain, however. TPA exists outside the brain cell, but the
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Contact: Andrew Klein
ank2017@med.cornell.edu
212-821-0560
New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College
Source:Eurekalert

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