Gaining Passage

Tracking the "secret" messengers of the blood-brain barrier.

By Rhonda Hollen

For years, scientists have used the brain-as-computer analogy to understand the gathering and processing of bodily data sent to our brains from the body's vast network of nerves. Now, however, details are slowly emerging of a very different and perhaps equally important data stream to the brain.

A team of physician-scientists at the Pennington Biomedical Research Center are intent on understanding the nature and extent of this extremely rich information flow through passages of what is known as the "blood-brain barrier," or BBB. The BBB is a complex neurovascular interface where the bloodstream comes into contact with the brain, much like a vast network of security checkpoints where a steady flow of chemical messengers arrive through the bloodstream, trying to gain clearance to the brain's various command centers.

And Dr. Abba J. Kastin and Dr. Weihong Pan are two scientists capable of sharing the strange combination of wonder and delight inspired by the mysteries of the BBB.

Kastin and Pan seem unlikely research partners. Calm, soft-spoken, Harvard-trained Kastin and fast-moving, engaging Pan met at Tulane University. Both were highly coveted researchers, well-funded, publishing new work and making waves in their field when they arrived at the Pennington Center late last year: Kastin a highly regarded, senior researcher with a career of recognized work, and Pan the shooting star post-graduate with an M.D. from Shanghai Medical University and a Ph.D. from Tulane.

Together they are unlocking the hidden secrets of the BBB and have made some important discoveries. Among them, that the BBB is not the static or motionless barrier it was thought to be; it is, in fact, an activity-filled, regulatory crossing point between blood and brain, deserving of more attention. According to Kastin, the BBB is a region of the brain comprised of a protective network of thin-walled blood vessels (capillaries) and tissue designed to protect the brain's sensitive periphery against harmful and toxic substances while allowing passage of critical chemical messages.

Kastin pioneered the concept that peptides in this periphery have central nervous system effects, an idea not accepted for decades . Now, Kastin and Pan have begun identifying key molecules that are quite adept at negotiating with and moving through the checkpoints of the BBB.

"We have focused on small proteins called peptides and polypeptides," explains Kastin. "We are finding that for some peptides entering the brain, there must be a by-passage based on chemical properties."

That is, the BBB recognizes specific molecules or their properties-not unlike secret codes-and allows them passage from the blood stream through the BBB to the brain or spinal cord.

According to Kastin, there are also active transport mechanisms that push polypeptides and peptides into the brain while allowing little transport out of the brain. This is important, because if drug researchers can develop compounds that follow the lead of these peptides, potentially life-saving medicines can be delivered into the brain and would remain there to do their work.

"The better the delivery, the better the chances," notes Pan. "In dealing with central nervous system disorders and side-effects of drugs, a key consideration is how much of the drug crosses the BBB."

Afflictions like stroke, spinal cord injuries, and even brain tumors are difficult to treat, because current chemotherapy lacks the messages to "trick" the BBB into allowing them access. To eventually help molecular messengers, including medicines, make their way through the BBB to the brain, investigators will have to act as biochemical negotiators, placing themselves between molecules and the BBB, learning the codes that will pass them on and increase the likelihood of entry. The ultimate reward is that if affordable medicines are able to successfully traverse the BBB and make their way into the brain and spinal cord, doctors could have better treatments for many of today's most debilitating illnesses.