Several new studies of the blood-brain barrier may pave the way for better treatments of certain cancers and inflammatory brain disorders such as Alzheimer’s disease and stroke.
The blood-brain barrier (BBB) is a network of specialized blood vessels that both transports nutrients into the neural tissue from the bloodstream and blocks potentially harmful substances.
“The easiest way to define the BBB is conceptually,” says William A. Banks, a researcher at Saint Louis University. “The name implies a barrier, and at that level it is just that—a barrier that makes sure that things that are in the brain stay in the brain and things that are in the blood stay in the blood without the free leakage one sees in other tissues.”
For the past century, scientists had little understanding of how the BBB developed or functioned, and it has remained a significant obstacle to drug therapy for neurological diseases. But the recent work suggests a method to short-circuit the growth of brain tumors as well as new ways to circumvent the barrier and deliver protective drugs to the brain.
Understanding BBB development
More than 20 years ago, cancer researchers learned that turning on certain genes in animals would result in tumors. Among these is WNT1, part of a family of genes that make up a complex signaling pathway involved in embryo development and cellular differentiation.
“WNT was originally studied largely in the area of oncology,” says Paul Polakis, a molecular oncologist with Genentech. “But it became clear that knocking out this gene also had dramatic effects on the brain, particularly defects in brain development.”
Now two studies, published in the Journal of Cell Biology and Science, respectively, have demonstrated that the WNT signaling pathway is responsible for the vascular development of the blood-brain barrier.
Stefan Liebner, a researcher at the University of Frankfurt, and colleagues inhibited the WNT signaling pathway in living animals to see its effect on embryonic development.
“We’ve known that the BBB does not exist in the premature brain but rather the blood vessels develop these specific characteristics as the brain grows,” he says. His lab found that the WNT signaling pathway played a key role in the development of the BBB by tightening up the endothelial cells, or the cells that line the interior of blood vessels.
In a complementary study, Jan Stenman, a researcher at the Ludwig Institute for Cancer Research in Stockholm, Sweden, and colleagues identified two growth factors, WNT7a and WNT7b, as responsible for BBB development.
Stenman argues that these findings, though preliminary, offer researchers new directions for treating many diseases. Potential applications include preventing the vascular development of brain tumors as well as finding new ways to allow blocked pharmaceutical treatments across the BBB, he says.
Using the brain’s natural neuroprotectants
Banks is also studying the BBB—but instead of focusing on development, he and his colleagues have identified a way to introduce a naturally occurring neuroprotectant, pituitary adenylate cyclase-activating polypeptide 27 (PACAP27), to the brain through the BBB. A recent study published in the Journal of Cerebral Blood Flow & Metabolism shows that this neuroprotectant may be a potent weapon against certain neuropathologies.
“PACAP is a very powerful neuroprotectant,” he says. “If you give it to animals that have had a stroke, it will protect the brain. Same for when you give animals HIV or other viral proteins toxic to the nervous system.”
But the BBB uses a specific transporter to keep PACAP27 out. So Banks and his collaborators developed an RNA “antisense” drug, which blocks the synthesis of the interfering transporter, in animal models of both Alzheimer’s disease and stroke. They found that in both cases PACAP entered the brain and reversed the symptoms of the illness.
“It’s fascinating,” Banks says, “because these data suggest that Alzheimer’s is not just preventable but a curable disease.” He argues that the development of other specific transporter antisense molecules may be the key to future treatment of brain pathologies.
All of these studies show promise for potential treatments. But Polakis cautions that there is still much work to be done.
“It’s an interesting story,” he says. “The WNT pathway activates some cancers. But in the case of inflammatory brain diseases, we see some suppression or inhibition of the same pathway that contributes to these diseases. It’s fairly self-evident that activating a cancer pathway to fix a neuronal disorder could have potentially negative consequences. But ultimately, that’s the challenge of applying this kind of work.”