Lowering The Brain’s Drawbridge | Chemical & Engineering News
Latest News
Web Date: September 20, 2011

Lowering The Brain’s Drawbridge

Drug Delivery: New technique shepherds large molecules across the blood-brain barrier in mice
Department: Science & Technology
News Channels: Biological SCENE
Keywords: drug delivery, blood-brain barrier
[+]Enlarge
Gate Crashers
With help from an adenosine analog, an antibody (pink) enters a mouse’s brain cells (blue, top). Without the analog, the antibody doesn’t enter (bottom).
Credit: Courtesy of Margaret Bynoe
Mouse brain cells strained with a blue dye called DAPI
 
Gate Crashers
With help from an adenosine analog, an antibody (pink) enters a mouse’s brain cells (blue, top). Without the analog, the antibody doesn’t enter (bottom).
Credit: Courtesy of Margaret Bynoe

By activating a biochemical signaling pathway, researchers have toppled the barrier that regulates molecules’ entry into the brain (J. Neurosci., DOI: 10.1523/jneurosci.3337-11.2011). The find could lead to more effective drug delivery options for Alzheimer’s disease or brain tumors.

The so-called blood-brain barrier is a tight-knit layer of specialized cells designed to shut out most molecular visitors to the brain. Medicinal chemists can circumvent the barrier by tweaking drug candidates, but such efforts don’t always succeed in treating the intended diseases successfully. Moreover, generalized options for traversing the barrier are limited.

Now, Margaret S. Bynoe of Cornell University College of Veterinary Medicine and colleagues show that receptors responding to the adenosine triphosphate metabolite adenosine act as a drawbridge for the brain. In mice, they activated adenosine receptor signaling with small-molecule adenosine analogs, including the FDA-approved imaging agent Lexiscan. This opened the brain barricade long enough to allow entry to antibodies or fluorophore-labeled polysaccharides. The length of time the barrier remained open was related to the adenosine analogs’ half-lives in the mice.

Antibodies nearly always get turned away at the brain’s proverbial castle gate, says Quentin R. Smith, a blood-brain barrier expert at Texas Tech University Health Sciences Center. With Bynoe’s technique, “you could open the gate and let the barbarians flood in, and then close the gate to trap them inside,” he says.

Still, Smith says caution is in order when evaluating a general method to penetrate the brain’s defenses. He says it’s important to find out whether deleterious molecules enter the brain when the barrier is compromised, whether altering fluid balance leads to brain swelling, and whether the strategy can also neutralize pump proteins that actively eject compounds from brain cells. “That is the real barrier for many lipophilic small drug compounds,” Smith says of the pump proteins.

“We have just scratched the surface,” Bynoe says. “There is so much to do.” Bynoe has patented the discovery and cofounded a start-up company, Adenios, in Ithaca, N.Y., to further develop the concept. Future experiments in her own lab will test the technique in mice with Alzheimer’s disease.

 
Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society

Leave A Comment

*Required to comment