Study reveals a potential target for stroke treatment in blood-brain barrier – About Your Online Magazine


Strokes are a major cause of poor quality of life or even death in Japan and around the world. Since its characterization, several researchers have been working with nails and teeth to identify effective and accessible therapeutic targets for drugs for this debilitating condition. One of these regions of interest for drug targets is the blood-brain barrier (BBB).

BBB is a structure located around the brain that prevents unnecessary circulating cells and biomolecules from entering the brain. BBB’s blood vessels are lined with a distinctive and protective layer of sugar, called the endothelial glycocalyx, which prevents its entry.

However, in the case of a stroke, which results in the blocking or rupture of blood vessels in the brain, studies have shown that this glycocalyx and, in turn, the integrity of the BBB are compromised. In addition, damage to blood vessels leads to neuronal death and an increase in toxic by-products such as acrolein.

A group of researchers from Japan and the United States wanted to explore how glycocalyx degradation occurs during an ischemic stroke.

When brain tissue becomes necrotic due to ischemia, the BBB’s function is disrupted and immune cells infiltrate the brain, exacerbating inflammation, but the details of this process are still unclear. “

Kyohei Higashi, junior associate professor, Tokyo University of Science

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 the accumulation of acrolein to changes in the glycocalyx, which results in damage to the BBB.

The team, also composed of Naoshi Dohmae and Takehiro Suzuki of the RIKEN Center for Sustainable Resource Science, Toshihiko Toida of Chiba University, Kazuei Igarashi of the Amine Pharma Research Institute, Robert J. Linhardt of the Rensselaer Polytechnic Institute and Tomomi Furihata of the Tokyo University of Pharmacy and Life Sciences, used rat models of stroke, as well as in vitro experiments (“in the laboratory”) using brain capillary endothelial cells to accurately study the mechanisms behind the BBB breakdown.

The researchers initially identified that the main sugars in the glycocalyx, heparan sulfate and chondroitin sulfate, showed decreased levels in the ‘hyperacute phase’ after a stroke. They also found increased activity of enzymes that degrade glycocalyx, such as hyaluronidase 1 and heparanase. After further investigation 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 modified specific amino acids in the structure of proHPSE, activating it. They concluded that this mechanism possibly led to the degradation of the glycocalyx and the subsequent rupture of the BBB.

The team’s discovery is critical, since acrolein-modified proHPSE may be a new and potentially effective drug target for post-stroke inflammation. As Dr. Higashi, who is also the study’s corresponding author, speculates: “Since proHPSE, but not HPSE, locates external cells by binding to heparan sulfate proteoglycans, acrolein-modified proHPSE represents a promising target for protecting the endothelial glycocalyx. “

In fact, we hope that further investigation of this mechanism will lead us to more effective therapies to combat stroke-related illnesses!

Source:

Newspaper reference:

Ko, K., et al. (2020) Ischemic stroke interrupts the endothelial glycocalyx by activating proHPSE by exposure to acrolein. Journal of Biological Chemistry. doi.org/10.1074/jbc.RA120.015105.

Paula Fonseca