Stroke of Luck: Scientists Discover Target for Stroke Therapy in Blood-Brain Barrier
Stroke is one of the leading causes of poor quality of death in Japan and around the world. Since its characterization, several researchers have been working to identify effective and accessible therapeutic targets for this disease. The blood-brain barrier (BBB) is one such region of interest for drug targets.
The blood-brain barrier
The BBB is a structure around the brain that prevents the entry of unnecessary circulating cells and biomolecules into the brain. The blood vessels of the BBB are covered with a distinct and protective sugar layer called endothelial glycocalyx, which prevents their entry. However, in the event of a stroke, which results in blocked or ruptured blood vessels in the brain, studies have shown that this glycocalyx degrades the integrity of the BBB. In addition, blood vessel damage leads to neuronal death and the accumulation of toxic byproducts such as acrolein.
A group of researchers from Japan and the United States wanted to study how glycocalyx degradation occurs during ischemic stroke. Kyohei Higashi, Junior Associate Professor at Tokyo University of Science, explains: "When brain tissue is necrotic due to ischemia, the function of the BBB is disrupted and immune cells infiltrate the brain, exacerbating inflammation, but the details of this process are not yet clear.
Studying the degradation of the BBB
For the first time, the group of scientists, led by Dr. Higashi, has identified a possible mechanism that links acrolein accumulation to changes in glycocalyx, leading to damage to the BBB. Researchers used mouse models of stroke as well as in vitro experiments using brain capillary endothelial cells to investigate precisely the mechanisms causing BBB degradation.
Researchers first identified that the major sugars in glycocalyx, heparan sulfate and chondroitin sulfate, had reduced levels in the "hyperacute phase" after stroke. They also found increased activity of glycocalyx-degrading enzymes such as hyaluronidase 1 and heparanase.
After further in vitro investigations using cell lines, they found that exposure to acrolein resulted in activation of the heparanase precursor (proHPSE). Specifically, they found that acrolein altered specific amino acids on the structure of proHPSE by activating it. They concluded that this mechanism may have led to the degradation of glycocalyx and subsequent disruption of the BBB.
A new drug target
The team's discovery is critical because acrolein-modified proHPSE may be a new drug target that could be potentially effective in post-stroke inflammation. As explained by Dr. Higashi, who is also the corresponding author of this study, "Because proHPSE, but not HPSE, localizes external cells by binding to heparan sulfate proteoglycans, acrolein-modified proHPSE represents a promising target to protect endothelial glycocalyx.
We hope that further research into this mechanism will lead to more effective therapies for stroke-related diseases," the researchers note.
