The brain is composed of billions of neuronsvulnerable cells that require a protective environment to function properly. This sensitive environment is protected by a 400 mile of specialized vasculature designed to limit substances that come into contact with the brain. But this blood-brain barrier is essential for protecting the organ from harmful chemicals and pathogens. In the context of neurological disease,Anne Eichmann, PhD, is the second author of cellular and molecular physiology, and claims that therapeutic drugs are not only prohibited
The Eichmanns team has developed an antibody as a tool for opening the blood-brain barrier for a couple of hours at a time, allowing for the delivery of drugs to a diseased brain. InNature Communicationson March 4, the company announced the findings.
According to Eichmann, the research''s senior author, this is the first time we have discovered how to control the blood-brain barrier with a molecule.
Rigorous basic research finds the key
The construction and maintenance of the blood-brain barrier are dependent on what is called the Wnt signaling pathway, which regulates a number of important cell processes. Eichmanns team was looking to determine if this pathway may be altered to allow the barrier on-demand.
After Kevin Boye''s contract with Yale University and the first author of the study, he decided to study a molecule known as Unc5B, an endothelial membrane receptor, which was expressed in the endothelial cells of capillaries in mice. This included, in the study, a researcher discovered that a protein known as Claudin5 which is also important in vascular development. This led the researchers to realize that the receptor may be important in maintaining this barrier.
There was previously no connection between Unc5B and the Wnt signaling pathway. Through this new study, the researchers discovered that the Unc5B receptor has been placed on the pathway, working as an downstream regulator.
It was a humbling journey, e.g., the development of our blocking antibodies and seeing that we can open the blood-brain barrier in a time-sensitive manner to encourage drug delivery.
Boye first found out that the receptor was absent in adult mice with an already established blood-brain barrier. Then, he determined which receptors which bind to receptors and send signals between or inside cells were also responsible for the barrier effect. Finally, he discovered that one ligand, Netrin-1, caused a blood-barrier flaw when it was removed.
The group developed a virus that might prevent Netrin-1 from binding to its receptor upon the injection. Upon injecting the antibody, the team was able to disrupt the Wnt signaling pathway, causing the blood-brain barrier to open temporarily on demand.
Boye says that it was a tremendous journey, especially the development of our blocking antibodies. And seeing that we can open the blood-brain barrier in a very time-sensitive way to promote medication delivery.
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Because the blood-brain barrier prevents entry to all but a small subset of small molecules, neurological conditions such as Alzheimers, multiple sclerosis, brain tumors, and depression are exceedingly difficult to treat. In future drug delivery endeavors, the team will identify any potential difficulties, but hopes to assess the effectiveness and potential toxicity of the antibody.
According to Eichmann, this opens the way for more interesting basic research on how the body creates such a tight barrier to protect its neurons and how can it be manipulated for drug delivery purposes. Finally, there''s the possibility to use this as a delivery platform for drugs to enter the brain.
The group hopes to examine how to apply its findings to chemotherapy treatment for brain tumors. They are also currently looking to see if their antibody may be applied to other areas of the central nervous system outside the brain.