Unlocking Blood Brain Barrier
Researchers in the fields of neurology and vascular biology have been searching for the magic solution to temporarily open and reseal the barrier to drug delivery for many years. The so-called Wnt Signaling Pathway, which controls a variety of critical cellular processes, is necessary for the formation and maintenance of the blood-brain barrier. Although the blood-brain barrier is an important evolutionary mechanism that safeguards the central nervous system, it also poses a significant barrier to the delivery of medicinal substances into the brain. For the treatment of a variety of conditions including brain cancer, stroke, and Alzheimer’s disease, it may be possible to get medication across the barrier and into the brain by blocking the function of Mfsd2a.
In order to maintain the blood-brain barrier’s impermeable character, one study reveals a precise molecular mechanism for how low rates of transcytosis are achieved in blood vessels of the central nervous system. We still don’t fully understand how the barrier is controlled. We can start to manipulate it with a better understanding of the mechanisms in order to deliver medications to the brain safely and effectively.
Endothelial cells, which coat the blood arteries in the central nervous system, form the blood-brain barrier. Tight connections between these cells block the passage of most chemicals, including many medications that treat brain illnesses. The Mfsd2a gene and the protein it encodes are essential for maintaining the blood-brain barrier because they prevent transcytosis. Despite having typical tight junctions, mice lacking Mfsd2a, a protein that is only found in endothelial cells in the central nervous system, exhibited increased rates of vesicle generation and leaky barriers.
Mfsd2a is a transporter protein that carries lipids containing DHA into the cell membrane. DHA is an omega-3 fatty acid that can be found in fish oil and nuts. A single amino acid mutation in the mutant version of Mfsd2a rendered it incapable of transporting DHA, which was used to investigate the significance of this function to the barrier in mice. When these mice were given an injection of a fluorescent dye, leaky blood-brain barriers and greater rates of vesicle production and transcytosis were seen, echoing those seen in mice wholly deficient in Mfsd2a.
Comparing the lipid composition of endothelial cells in lung capillaries, which lack barrier characteristics and do not express Mfsd2a, to those in brain capillaries indicated that DHA-containing lipid levels were two to five times greater in the latter. More research showed that Mfsd2a inhibits transcytosis by preventing the development of caveolae, a type of vesicle that develops when a tiny portion of the cell membrane pinches in on itself. As expected, mice lacking Mfsd2a but with normal Cav-1, a protein necessary for the development of caveolae, showed greater transcytosis and leaky barriers. However, mice lacking both Cav-1 and Mfsd2a had modest levels of transcytosis and impenetrable blood-brain barriers.
Adult mouse tests confirmed that the blood-brain barrier is really left open when Unc5B is absent. The researchers then discovered the Netrin-1 ligand, a binding molecule, which regulates Unc5B’s effectiveness. Finally, an antibody to inhibit Netrin-1 and the Wnt pathway was created.
This is the first time that Unc5B has been connected to the operation of the Wnt signaling pathway, which is an interesting breakthrough given that it may make it possible to treat a variety of brain-related disorders.
But there is still work to be done. The antibody’s efficacy is still being studied, and researchers will be keeping an eye out for any toxicity or side effects that would make this method of medication delivery challenges.
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