Antioxidant Peptide Could Help Minimize Stroke-Linked Brain Damage

"In our experiments, we found that exposing mice to SS31 after an induced ischemic stroke led to a much smaller area of brain tissue being affected,” stated the study's lead investigator Dr. Sunghee Cho, assistant research professor of neuroscience at Weill Cornell University Medical College (New York, NY, USA). Dr. Cho is also assistant professor of neurology/neuroscience and director of preclinical stroke modeling at the Burke Medical Research Institute (White Plains, NY, USA).

The new study suggests that SS31 works by suppressing the activity of CD36, a "scavenger” receptor that Dr. Cho and her colleagues in the department of neurology/neurobiology at Weill Cornell Medical College have previously linked to stroke-induced tissue damage. The findings were published in the February 2007 issue of the Journal of Biological Chemistry.

Each year, millions of Americans are affected by strokes or transient ischemic attacks (TIAs), also called "mini-strokes.” Damage to brain tissue occurs not just during the blockage itself, but after the blockage is cleared, as blood rushes back to the site in a process known as reperfusion. "Reperfusion creates a lot of oxidative stress and related damage to neural tissues,” explained study senior author Dr. John Pinto, a research scientist at Burke. "A lot of that damage seems to be caused by a heightened activity of CD36.”

Therefore, the researchers tried to see if there was a molecule that can reach the stroke site and keep CD36 from acting as it does. Fortunately, another researcher at Weill Cornell, professor of pharmacology Dr. Hazel Szeto, had already developed a candidate antioxidant peptide, SS31. Dr. Szeto is a co-researcher on the current study. "Dr. Szeto was, in fact, looking for a model of ischemia to test out SS31,” Dr. Cho said. "Since we knew the molecule could pass through the blood-brain barrier--something most drugs cannot do--SS31 seemed to be a perfect fit.

In their study, the Weill Cornell team induced ischemic stroke in mice, then treated the mice soon after with SS31.The results were impressive. "The size of infarct--tissue damage--in the mouse brain cortex was significantly reduced in the treated vs untreated animals,” Dr. Pinto said.

Another promising sign: the procedure produced high brain levels of an oxidative stress marker called glutathione, which is typically depleted in areas affected by stroke/reperfusion. "If you have a stroke, you lose glutathione very quickly,” Dr. Cho said. "That happened in the untreated mice, but SS31 seemed to keep glutathione levels relatively high in the treated animals.”

To help find out how SS31 was working, the team tested the drug in mice genetically modified to lack functioning CD36. "For these mice, treatment with SS31 after stroke had no effect,” Dr. Cho remarked. "That suggests that this peptide is working via inhibiting CD36 pathways.”

The exact mechanism by which SS31 inhibits CD36 remains unclear, she said. "We have theories--for example, it may block binding of CD36 with LDL cholesterol, reducing LDL oxidation. But there could be multiple pathways. We just don't know.”

The researchers stressed that human stroke is much more complex than that seen in mice, so the real benefit of SS31 as a stroke-limiting drug remains to be seen. Still, they are optimistic. "Right now, stroke patients have very limited treatment options, so an effective agent that could reach the site of injury and lessen damage would be a great advance,” Dr. Cho stated.


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