THE strokes (Stroke) are extremely common, occurring every 4 minutes in France and causing 30,000 deaths per year and causing potentially serious after-effects in the thousands of survivors. The majority of strokes are ischemic, meaning they are caused by a blood clot that blocks an artery supplying the brain. The brain tissue is therefore no longer oxygenated and dies quickly. Currently, treatments for these ischemic strokes consist of undoing the blood clot blocking the artery, to allow blood to pass and supply the brain with oxygen and nutrients, and thus stop the damage. A new drug could complement this treatment, by reducing the oxidative stress caused by the process of ischemia and reperfusion (when blood can flow again) and thus reducing brain damage. This new treatment was presented on June 20, 2025 by researchers from Osaka University, Japan, in iScience.
Preventing aggregation of a metabolic protein during stroke
A previous study by the same team had shown that oxidative stress caused by a stroke led to the aggregation—that is, the formation of abnormal clumps—of a key metabolic protein: GAPDH (glyceraldehyde-3-phosphate dehydrogenase).
This enzyme plays a central role in glycolysis, the process by which glucose is broken down to produce energy, but it is also involved in other essential functions, such as DNA repair. To determine whether this aggregation contributes to brain damage caused by stroke, the researchers conducted an experiment on mice. In these animals, a cerebral artery was blocked for 30 minutes, followed by reperfusion (restoration of blood flow). One group of mice had been genetically modified to produce a version of GAPDH that cannot aggregate. As a result, the area of damaged brain tissue was twice as large in unmodified mice. This suggests that GAPDH aggregation could amplify stroke-related damage.
Additionally, mice protected from aggregation exhibited less mitochondrial dysfunction. However, these organelles, the cell's true "powerhouses," are also a major source of oxidative stress when they malfunction. Preventing GAPDH aggregation would therefore preserve mitochondria, limit oxidative stress, and, consequently, reduce the damage caused by stroke.
A drug to prevent this aggregation and protect the brain
Since stroke sufferers cannot be genetically modified, researchers have found a way to prevent these aggregations pharmaceutically. The molecule used, called GAI-17, is a GAPDH inhibitor that attaches to the site of the protein where it adheres to other copies of GAPDH, blocking aggregation.
The mice were treated one hour before the stroke was induced, halving the damage caused by the event and improving mitochondrial function compared to untreated mice. But what's most interesting is that this molecule was just as effective, even after the stroke: mice treated 3 or 6 hours after the event showed less neuronal damage than untreated mice. In contrast, the same treatment administered 9 hours after the stroke no longer had a protective effect, confirming the importance of acting quickly.
Now, the researchers want to test this molecule in other contexts where oxidative stress can harm brain health: “We hope that this GAPDH aggregation inhibitor can be used to treat other neurological diseases as well, including Alzheimer's disease.”, says Hidemitsu Nakajima, director of the study, in a press release. These are high expectations, which require further studies to be confirmed.
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