Stroke of luck: therapeutic target discovered in the blood-brain barrier

The blood-brain barrier prevents immune cells from moving freely in the brain, and the degradation of its function is a major cause of post-stroke inflammation. Today, for the first time, researchers have identified how a toxic stroke byproduct, acrolein, could activate the barrier degrading enzyme proheparanase (proHPSE). The research group found that proHPSE breaks down glycocalyx in post-stroke brain blood vessels, offering hope for new effective therapies for post-stroke inflammation.

Stroke is one of the leading causes of poor quality of life or even death in Japan and around the world. Since its characterization, several researchers have worked tooth and nail to identify effective therapeutic targets and accessible to drugs for this debilitating disease. One such region of interest for drug targets is the blood-brain barrier (BBB).

BBB is a structure around the brain that prevents unnecessary circulating cells and biomolecules from entering the brain. The blood vessels of the BBB are covered with a separate and protective layer of sugar, called endothelial glycocalyx, which prevents their entry. However, in stroke, which results in the blockage or rupture of blood vessels in the brain, studies have shown that this glycocalyx and, in turn, the integrity of BBB, is compromised. Additionally, damage to blood vessels leads to neuronal death and the build-up of toxic byproducts like acrolein.

A group of researchers from Japan and the United States wanted to explore how glycocalyx degradation occurs during ischemic stroke. Tokyo University of Science Junior Associate Professor Kyohei Higashi, one of the researchers, explains the motivation behind the research, “When brain tissue becomes necrotic due to ischemia, BBB function is disrupted and immune cells infiltrate the brain, exacerbating inflammation, but the details of this process are still unclear. For the first time, as detailed by the study published in Journal of Biological Chemistry, the group of scientists, led by Dr. Higashi, identified a possible mechanism that links acrolein build-up to changes in glycocalyx, resulting in damage to the BBB. The team, also including Naoshi Dohmae and Takehiro Suzuki from the RIKEN Center for Sustainable Resource Science, Toshihiko Toida from Chiba University, Kazuei Igarashi from the Amine Pharma Research Institute, Robert J. Linhardt from the Rensselaer Polytechnic Institute and Tomomi Furihata from Tokyo University of Pharmacy and Life Sciences, used racing mouse models as well as in vitro (“laboratory”) experiments using brain capillary endothelial cells to accurately study the mechanisms behind the degradation of BBB.

Researchers initially identified that the major sugars in glycocalyx, heparan sulfate and chondroitin sulfate, showed decreased levels in the “hyper-acute phase” after a stroke. They also found the increased activity of glycocalyx-degrading enzymes like hyaluronidase 1 and heparanase. Further in vitro using cell lines, they found that exposure to acrolein led to the activation of the heparanase precursor (proHPSE). Specifically, they found that acrolein altered specific amino acids on the structure of proHPSE, activating it. They concluded that this mechanism may have led to the degradation of glycocalyx and subsequent disruption of BBB.

The team’s discovery is critical, as acrolein-modified proHPSE could be a potentially effective new drug target for post-stroke inflammation. As Dr Higashi, who is also the corresponding author of the study, speculates, “Because proHPSE, but not HPSE, localizes outer cells by binding to heparan sulfate proteoglycans, acrolein-modified proHPSE represents a promising target for protecting the endothelial glycocalyx.”

Indeed, we hope that the further study of this mechanism will lead us to more effective therapies to fight against stroke-related diseases!

Reference: Ko K, Suzuki T, Ishikawa R et al. Ischemic stroke disrupts the endothelial glycocalyx by activating proHPSE via exposure to acrolein. J. Biol. Chem. 2020; 295 (52): 18614-18624. do I:10.1074 / jbc.RA120.015105

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