Scientists have discovered an effective therapeutic target for life-changing strokes which could help improve quality of life for patients.
A new study has shown that a stroke byproduct called acrolein activates the precursor of heparanase, an enzyme that degrades the glycocalyx (a protective layer of sugar) in the blood-brain barrier, which prevents the entry of unnecessary circulating cells and biomolecules into the brain. The researchers from Japan and the United States wanted to explore how the degradation of the glycocalyx takes place during an ischemic stroke, discovering the therapeutic target for treatment.
In the event of a stroke, which results in the blockage or severance of blood vessels in the brain, glycocalyx and the integrity of the blood brain barrier are compromised and damage to the blood vessels leads to neuronal death and the build-up of toxic byproducts like acrolein.
The study has been published in the Journal of Biological Chemistry.
Breakdown of the blood brain barrier
The scientists, led by Researcher and Junior Associate Professor Kyohei Higashi from Tokyo University of Science, have identified a possible mechanism that links acrolein accumulation to glycocalyx modifications, which results in damage to the blood brain barrier. They used mouse models of stroke as well as in vitro experiments using cerebral capillary endothelial cells to accurately study the mechanisms behind the breakdown.
Dr Higashi said: “When brain tissue becomes necrotic due to ischemia, the function of the blood brain barrier is disrupted and immune cells infiltrate the brain, exacerbating inflammation, but the details of this process are still unclear.”
The researchers initially identified that the major sugars in the glycocalyx – heparan sulphate and chondroitin sulphate – showed decreased levels in the ‘hyperacute phase’ after a stroke and found increased activity of glycocalyx-degrading enzymes like hyaluronidase 1 and heparanase.
Using cell lines, the team found that acrolein exposure led to the activation of the precursor of heparanase (proHPSE), specifically, that the acrolein modified specific amino acids on the structure of proHPSE, activating it. They concluded that this mechanism possibly led to the degradation of the glycocalyx, and the subsequent disruption of the BBB.
Dr Higashi, who is also the corresponding author, said: “Because proHPSE, but not HPSE, localises outside cells by binding with heparan sulphate proteoglycans, acrolein-modified proHPSE represents a promising target to protect the endothelial glycocalyx.”
The team hope that further investigation of this mechanism will lead to therapies that are more effective in tackling stroke-related illnesses.