Emory Report

September 11, 2000

 Volume 53, No. 3

Emory pair traces brain damage caused by stroke

By Holly Korschun

Increased scientific evidence demonstrates that serine proteases­­a group of enzymes involved in blood clotting­­may enter the brain during traumatic head injury and stroke, leading to enhanced brain damage.

In the September issue of Trends in Neuroscience, Emory neuroscientists Stephen Tray-nelis and Melissa Gingrich outlined growing evidence for the role of serine proteases in brain tissue scarring (glial scarring), edema (swelling), seizure and neuronal cell death.

The pair recently uncovered clues to a complex brain pathway that may help explain why individuals suffer seizures and brain damage during stroke. They found that the PAR1 receptor­­a receptor for the protease thrombin-stimulates brain receptors already implicated in cell degeneration and cell death during stroke. The scientists believe that following activation of the thrombin-PAR1 pathway during stroke, these receptors could further exacerbate the brain damage that occurs.

Although proteases involved in blood clotting normally would not enter the brain because of the tight blood/brain barrier, during a stroke thrombin and other proteases, including tissue plasminogen activator (tPA) and plasmin could enter the brain as the blood/brain barrier breaks down, Traynelis said.

During a hemorrhagic stroke (in which there is excess bleeding) or during an ischemic stroke (caused by a blood clot), the brain and vascular system are deprived of the energy necessary to maintain the strict separation normally maintained between blood and brain.

Serine proteases are able to cleave (split in two) larger proteins, which sets off a domino-like cascade of signals as each protein clips the subsequent one. During this signaling process, thrombin activates the PAR1 receptor. Traynelis believes the potential increase in stroke damage caused by thrombin and other proteases and their receptors may be partly explained by the recent finding that these proteases and their receptors also are produced in the brain itself.

Recent evidence suggests that thrombin, plasmin, tPA and other proteases and their receptors may be part of a highly regulated neuro-signaling pathway in the brain. If these same proteases from the blood cross the blood/brain barrier during stroke or head trauma, they could severely disrupt this neurological pathway, causing overactivation of parts of the brain.

Thrombin has been found in mice to play a role in the formation of glial scars, often associated with brain injury. It also has been found to trigger swelling in the brain, which can damage brain tissue. Seizures that occur following stroke and brain injury are associated with hemorrhage into brain tissue, and scientists postulate that PAR1 activation in the brain is at least partly responsible.

"More and more pieces of these protease pathways are being uncovered, increasing the evidence that serine proteases that cross the blood/brain barrier expand damage in some forms of stroke and head trauma," Traynelis said. "Future studies will need to concentrate on the mechanisms that serine proteases and their receptors use to enter brain tissue and to determine whether the brain contains additional protease receptors or proteins that can interact with serine proteases to exacerbate damage."

Findings that the thombin-PAR1 pathway and other protease pathways are involved in increasing the negative effects of brain injury could eventually lead to the development of drugs that block the function of these proteases and thus protect brain cells, he added.

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