A novel peptide discovered by researchers at Weill Cornell Medical College could prove a potent weapon against stroke, a new study// finds.
The compound, called SS31, is able to cross the blood-brain barrier and inhibit an oxidative stress molecule recently linked to stroke-related tissue 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," says the study's lead author Dr. Sunghee Cho, assistant research professor of neuroscience at Weill Cornell Medical College. Dr. Cho is also assistant professor of neurology/neuroscience and director of preclinical stroke modeling at the Burke Medical Research Institute in White Plains, N.Y.
The new study suggests that SS31 works by inhibiting 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 recently published in the Journal of Biological Chemistry.
Each year, millions of Americans are affected by strokes or "transient ischemic attacks," otherwise 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," explains 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."
So, the question was: Is there a molecule that can reach the stroke site and keep CD36 from acting as it does
Luckily, 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 paper.
"Dr. Szeto was, in fact, looking for a model of ischemia to test out SS31," Dr. Cho says. "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 experiments, 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 says.
Another promising sign: high brain levels of an oxidative stress marker called glutathione, which is usually depleted in areas affected by stroke/reperfusion.
"If you have a stroke, you lose glutathione very quickly," Dr. Cho says. "That happened in the untreated mice, but SS31 seemed to keep glutathione levels relatively high in the treated animals."
But how was SS31 working its magic? To help find out, the team tested the drug in mice genetically engineered to lack functioning CD36.
"For these mice, treatment with SS31 after stroke had no effect," Dr. Cho says. "That suggests that this peptide is working via inhibiting CD36 pathways."
The exact mechanism by which SS31 inhibits CD36 remains unclear, she says. "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 true value 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 says.
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