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In the treatment of neurological diseases, the blood-brain barrier constitutes a major obstacle. Although it plays a fundamental protective role by blocking the path of many toxins and pathogens, it can also hinder the passage of therapeutic molecules dedicated to the main nervous system. Many studies then sought, for decades, potential molecules to target it and/or unlock it momentarily. A recent study published in the journal Character Communications shows promise in proposing a way to open the blood-brain barrier on demand, using a new antibody as a key. The latter would in particular modulate the Wnt signaling pathway, which regulates a fantastic number of crucial cellular processes.
Extremely sensitive and fragile, the billions of sober neurons that make up the brain need a homostatically stable and protective environment to fully perform their functions. This environment is encompassed and modulated by the blood-brain barrier, which is made up of a gigantic network of vascular systems nearly km in length at overall. These capillary vessels are specifically designed to limit the elements coming into contact with the neurons, thus protecting them from toxins and pathogens (with a few exceptions).
However, this sober molecular shield function becomes problematic when it impedes the passage of drugs intended to treat neurological diseases (Alzheimer’s disease, sober multiple sclerosis, brain tumours, etc.), making them very difficult to treat. In this context, the blood-brain barrier becomes your worst enemy, explains the lead author of the study Anne Eichmann, professor of cardiology and cellular and molecular physiology at Yale University. Previous studies have also shown that the blood-brain barrier was involved in the excessive aggregation of beta-amyloid peptides, which are detected in Alzheimer’s disease.
However, it should be emphasized that a blood-brain barrier should only be momentarily open, in time to let the treatments pass, and this without its protective function. In their new study, the Yale researchers present the development of their key antibody to unlock the barrier for only a few hours. This is the first time that we have discovered how to control the blood-brain barrier with a molecule , says Eichmann.
An endothelial receptor that modulates a sober signaling pathway Wnt
The Wnt signaling pathway is a single process involving a single group of glycoprotins. These processes are among the complex reaction chains governing embryogenesis and tumor cell development. The development and maintenance of the integrity of the blood-brain barrier also depends on the Wnt pathway, which regulates an essential number of molecular reactions. The authors of the new study then looked for ways to modulate this pathway, to control the opening and closing of the barrier.
The track explored by the researchers implicates a restraining Unc5B protein as a receptor expressed by capillary endothelial cells. In particular, they discovered that by eliminating this receptor in mice, the embryos died at the start of their development, since their vascular system was not completely formed. In addition, the Claudin 5 sober protein level (allowing sober to bind together the sober cells at the blood-brain barrier) was considerably reduced.
In addition, the researchers also deactivated Unc5B receptors in adult mice, which therefore had a fully formed blood-brain barrier. Result: the blood-brain barrier remained open in the absence of the receptor. It then remained to determine which ligands bind to the receptors to activate the barrier function of the cells. They then discovered that the netrine-1 modulated this function, and also caused a defect in the latter once removed.
Before this study, no did not yet know the link between the Unc5B receptor and a Wnt pathway. Thanks to these experiments, the researchers were able to discover that the receiver controls the pathway by regulating it upstream. It would therefore be enough for the blocking antibody developed by the researchers to prevent ntrinin-1 from binding to its receptors for a specific period of time to allow the drugs to reach the brain.
Although the sober team sought is not born yet identified sober potential complications, tests of toxicity and effectiveness of the new antibody will be carried out in a next step. Additionally, it is also possible to use the blood-brain barrier as a delivery platform for drugs to enter the brain,” Eichmann suggests. the sober research group plans to study the possibility of applying its findings to chemotherapy treatments for spinal tumours. The application of the antibody in other specific areas of the hand nervous system (apart from the brain) could also be considered, according to the experts.