Heat Shock Protein Prevents Brain Damage

A protein made in times of cellular stress can protect the brain from damage induced by a stroke or seizure, Stanford researchers have demonstrated in gene-transfer experiments with rats. The protein, called heat shock protein 72 (HSP72), is produced by cells stressed by heat, chemicals or lack of nutrients. Researchers found that a modified herpes virus that makes the protein reduced nerve cell death when injected into rat brains.

"This is the first demonstration that gene transfer with this particular protein can protect the brain against injury in animal models," said Gary Steinberg, professor of neurosurgery and co-director of the Stanford Stroke Center.

Process

The Stanford team mimicked a stroke in rats by blocking blood flow to part of the brain. This reliably damaged the striatum, a region deep in the brain. Injection of the virus that makes HSP72 increased survival of nerve cells in the striatum from 62% in untreated rats to 95% in the treated ones, the researchers found. To model damage caused by seizures, they added kainic acid, which overstimulates the brain, especially the hippocampus. In this region, the team found that nerve cell survival increased from 22% to 64% when extra HSP72 was present.

Treatment prospects

Although the work is promising, Steinberg emphasized that translating the new findings into a practical treatment for stroke and other forms of brain damage will require a more efficient way to deliver the protein. In their study, the researchers had to deliver the virus by injection into the brain, and the virus did not spread far beyond the injection site. But the current work does strengthen the scientific rationale for pursuing a treatment based on HSP72, he said.

"Heat shock proteins are induced in stroke, but until now, no one knew what that meant - whether these proteins were just markers of cell death or if they were actually protective," Steinberg explained. "This is one of the first studies showing that producing extra heat shock protein causes protection."

Strokes start when wayward blood clots block a blood vessel, cutting off the supply of oxygen and nutrients to part of the brain. Without these energy sources, the nerve cells in that area release toxic chemicals, including oxygen radicals and excitatory amino acids. Eventually these nerve cells die. Brain seizures start similar cascades of cell death, Steinberg said.

Exactly how HSP72 intervenes in this process is not clear. In other cells, however, heat shock proteins are known to recognize and fasten onto damaged proteins, either helping the proteins to reshape themselves or escorting them to their destruction. Either action could help keep nerve cells alive.

Steinberg and his colleagues injected the HSP72-producing virus 12 hours before blocking a blood vessel or adding kainic acid. Such a preemptive procedure clearly is not possible for most real strokes, although it might prove useful in situations where a patient is known to be at high risk of brain damage. Brain surgery or cardiovascular surgery, for example, can sometimes lead to blockage of blood vessels, either deliberately by the surgeon or inadvertently by a clot that has been dislodged.

Next Step

To see whether a treatment could ever be developed for the more common, unpredictable form of stroke, Steinberg and his colleagues will now test whether injecting the virus after brain injury can help. Similar experiments with Bcl2—a protein that turns off the cell's suicide mechanism—have proved successful. In these earlier studies, Steinberg and collaborator Robert Sapolsky, a Stanford professor of biological sciences, found that injecting the virus that makes Bcl2 can reduce nerve cell death even when the virus is given hours after the brain injury.

For more information: Gary Steinberg, professor, Dept. of Neurosurgery, Stanford University Medical Center, 300 Pasteur Dr., Stanford, CA 94305. Email: mk.gks@forsythe.stanford.edu.