The Brain Impenetrable

The blood-brain barrier, which controls chemical traffic to and from the brain, may be even more complex than previously thought. Some compounds that appear to penetrate the entire brain, as indicated by brain scans, are in fact caught by a second line of defense. Experts say the findings, reported in the February American Journal of Neuroradiology, underscore the problem of delivering drugs against a variety of brain ailments such as stroke, brain tumors, and neurodegenerative diseases.

The blood-brain barrier isn't a filter at the base of your skull, rather it's a coating of cells that line hundreds of kilometers of blood vessels reaching every crevice of the cranium. These cells, called endothelial cells, are cemented together with gluelike substances in structures called tight junctions. Normally, only tiny, lipid-soluble molecules can seep through this barrier. Glucose and other necessary substances are shuttled across by specific carrier systems. For anything else, such as drugs or virus particles engineered to carry therapeutic genes, scientists must resort to a trick: Injecting a concentrated sugar solution makes the endothelial cells shrink, temporarily opening pores between the cells.

Using this technique, the team of neurosurgeon Edward Neuwelt at the Oregon Health Sciences University and the Veterans Administration Medical Center in Portland set out to develop a noninvasive way of monitoring the distribution of potential drugs. They injected rats with two kinds of sugar-coated iron oxide beads, about the size of viral particles commonly used for gene therapy. The team visualized the particles with magnetic resonance imaging, which suggested that both compounds spread evenly throughout the brain. But when Neuwelt looked at some brain preparations and slices under the microscope at a higher resolution, he was taken aback: One compound had passed the endothelial cells but was stuck in a complex mesh of sugar and protein fibers, called the basement membrane, surrounding the blood vessels. With most standard imaging techniques, Neuwelt says, this entrapment of some compounds in the "spider web of the basement membrane" might give you "the false view that you've got homogeneous delivery when in fact you haven't."

"The study shows that there's more to the blood-brain barrier than the tight junctions. It challenges the prevailing thinking," says neuroscientist Thomas Jacobs of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. The findings, Jacobs says, underscore the importance of setting aside more resources for the study of drug delivery, the "Achilles heel" of brain therapies. Neuwelt agrees: "Industry is spending hundreds of millions of dollars to develop new drugs [for the brain], yet virtually nothing at all on how to get them there." The next step, he adds, is to "figure out why some particles pass through and others don't."

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