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Scientists Use Human Brain Slices as Intermediate Step in Stroke Drug Discovery


Scientists at the Medical College of Georgia have received a two-year grant from the National Institute of Neurological Disorders and Stroke to use human brain slices to study the effects of candidate compounds as stroke therapies — an approach that the researchers believe can serve as an important intermediate step between animal studies and human clinical trials.

"Working with human tissue can help us to verify ideas that we got from experiments with animal tissue," Sergei Kirov, an associate professor in the department of neurosurgery at MCG and the principal investigator on the grant, told CBA News this week. "We can verify these ideas to see if we are on target or completely off base."

The grant, awarded in September and worth $193,000 for fiscal 2008, supports a project to use human neocortical slices to evaluate the ability of candidate compounds to prevent or delay anoxic depolarization, and evaluate at the cellular level the neuroprotective effects of these compounds during onset, and recovery from, AD-mediated injury.

A report published in November 2007 in Stroke noted that many potential stroke therapies found to be neuroprotective in rodents and animal studies failed when tried in clinical trials in humans. The paper outlined a roadmap that includes better proof of efficacy in animal models as well as studies in human brain tissue focusing on the penumbra.

"If we know of a couple of compounds that work in animals, for example, before advancing to clinical trials, we can use human brain slices to determine if we even go to patients," said Kirov.

Slice of Life

The brain slices for the project are obtained primarily from epilepsy surgeries performed at MCGHealth Medical Center and Children's Medical Center. Kirov said that one reason brain slices are a good model in which to simulate anoxic depolarization is "because we can maintain brain slices in vitro for about 8 to 12 hours, if it is a rodent slice for example," said Kirov. The human slices are about 400 µm thick and are maintained in a constant flow of artificial cerebrospinal fluid.

To simulate ischemic conditions similar to those that would occur during stroke, the researchers removed oxygen and glucose from this artificial CSF. To add oxygen to the solution, "we bubbled it into the solution, and to remove it, we bubbled in nitrogen," Kirov said. This created conditions of oxygen/glucose deprivation.

In about nine to 10 minutes, neurons and astrocytes became depolarized. That depolarization can be measured with electrophysiology, which is coupled with optical imaging.

The intrinsic light transmittance associated with anoxic depolarization can be very precisely measured by intrinsic optical imaging, said Kirov. "We can add drugs and see if the anoxic depolarization and associated neuronal swelling can be prevented or delayed," which can give investigators an idea of the efficacy of the drug. Different drugs can be tested at different concentrations.

In addition, Kirov said, "I can look at the effect of the drug on a single cell using a technique called two-photon laser scanning microscopy." In this case, a slice can be used as its own control because scientists can look at it before ischemic damage, during ischemic damage, and after.

"We just started to do work on this grant. When we get more money, we will decide what the next step should be. I think we will identify some promising substances," Kirov said.

Kirov said that his group is currently preparing a paper and that a grad student in his lab, Chris Risher, will be the first author.

Kirov said that the manuscript will likely be submitted by the end of April, although he was unsure to what journal. He also said that "it is difficult to say at this point" whether his group will license or commercialize this work.

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