Towards Repair of the Leaking Blood-Brain Barrier
Researchers here report on an effort to find small molecule drugs that can favorably adjust cell metabolism in the blood-brain barrier, in order to prevent some fraction of the dysfunction and leakage that occurs with age. The blood-brain barrier is a specialized layer of cells that controls the traffic of molecules between the bloodstream and brain tissue. With advancing age, it becomes less effective, allowing unwanted molecules and cells to leak into the brain to provoke chronic inflammation and other issues. Maintaining effectiveness of the blood-brain barrier could push back the onset of neurodegenerative conditions.
Researchers have evaluated a new therapeutic class of molecules that can be used to treat a leaky blood-brain barrier. The researchers started by looking at WNT signaling, a communication pathway used by cells to promote tissue regeneration and wound healing. WNT signaling helps maintain the blood-brain barrier by promoting cell-to-cell communication that lines brain blood vessels. Scientists have been focusing on frizzled, a protein receptor that initiates the WNT pathway, for blood-brain barrier therapies since mouse mutations in the frizzled gene cause blood-brain barrier abnormalities.
Many different molecules bind to frizzled protein receptors, such as the frizzled receptor FZD4, so to narrow their search for a potential therapeutic molecule, the researchers selected only those that specifically target cells that line the brain's blood vessels. Researchers created L6-F4-2, a FZD4 binding molecule that activates WNT signaling 100 times more efficiently than other FZD4 binders.
Researchers then studied models of ischemic stroke, in which blood vessels and the blood-brain barrier are damaged, and fluid, blood and inflammatory proteins involved in cellular communication can leak into the brain. They found that L6-F4-2 reduced the severity of stroke and improved survival of mice compared with mice that had untreated strokes. Importantly, L6-F4-2 reversed the leakiness of brain blood vessels after stroke. Mice treated with L6-F4-2 had increased stroke survival, compared to those that were not treated. The finding shows that, in mice, the blood-brain barrier could be restored by drugs that activate FZD receptors and the WNT signaling pathway.
Link: https://scopeblog.stanford.edu/2023/06/19/restoring-the-blood-brain-barrier/