January 24, 1997

Researcher studies new stroke damage culprit

Researcher studies new stroke damage culprit

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Todd Verdoorn, Ph.D., is studying the role glutamate receptors play in post-stroke cell death.

Much of the permanent damage done by a stroke is caused by the brain cells' resulting inability to produce energy due to a lack of oxygen and nutrients.

But a VUMC researcher is studying an additional mechanism that may kill brain cells after a stroke ‹ over-activation of glutamate receptors.

Found in high concentrations in the brain, glutamate receptors are one of the key signaling molecules for rapid communication between neurons.

In a strange biologic irony, these molecules responsible for cell communication may also kill cells following a stroke, said Todd A. Verdoorn, Ph.D., assistant professor of Pharmacology.

"When cells die they release glutamate. The parts of the brain that are near where the initial cells died because of the stroke are then overloaded with glutamate, and the overactive receptors kill those cells."

Following a stroke, the glutamate overload damage spreads, then eventually slows and is minimized. An understanding of how to disrupt the glutamate reaction before it spreads, however, would be very helpful to stoke victims.

Verdoorn is studying the way in which glutamate is used by neurons to facilitate communication, research that may lead to the further development of drugs to aid stroke patients by blocking the spread of cell damage.

Recently, Verdoorn received the Presidential Early Career Award for Scientists and Engineers from the National Science Foundation. The award recognizes the promise of future success in scientific and engineering research.

Normally, when one neuron talks to another it does so by means of the synaptic cleft, which is the small space between neurons. The sending neuron will release glutamate across the cleft to the receiving neuron's receptors. When the receptors sense enough glutamate, they open ion channels that allow positively charged sodium ions to enter the cell and excite it.

"It turns out that glutamate is responsible for almost all of the very rapid communication between that goes on in the brain, things that happen in the millisecond time scale," said Verdoorn. "They are the workhorses of rapid communication."

Much of Verdoorn's research is done on the glutamate binding pocket of the receptor. In order to study that pocket Verdoorn uses what is called a patch clamp.

The patch clamp uses a glass electrode to isolate a particular receptor by forming a seal around the receptor, allowing Verdoorn to manipulate what goes into the receptor. This tight seal also allows Verdoorn to measure the tiny electrical currents swirling within the receptor.

"The equipment we use is so sensitive that we can measure the current going through one of these at a time. The electrical current we are talking about is a billionth to one hundred times smaller that the current required to run a light bulb." said Verdoorn.

To further study glutamate receptors, Verdoorn not only studies them on their neuron but expresses them on cells that would not normally have them.

"The idea is to find out more about how the receptor molecule actually sees glutamate, the shape of the receptor and the steps between when the receptor sees glutamate and the generation of current," said Verdoorn.

This intense study coincides with the development of drugs to inhibit the reaction of glutamate after a stoke. Although the drugs are far from clinical trials, they are attractive because they allow for the possibility of patients to be given an injection after a stroke to minimize the damage to the brain.

"You can give these drugs in animal models up to 72 hours after a stroke and still protect some part of the brain," said Verdoorn. "What we are looking for is a drug that would minimize the long term damage."