SAN DIEGO - Neurons are in something of a "can't live with it, can't live without it" position as far as blood supply is concerned.

On the one hand, neurons guzzle energy like a Hummer guzzles gas. The brain, which makes up roughly 2 percent of an adult humans' body weight (and probably less, now that the obesity epidemic is in full swing) uses up 20 percent of its oxygen.

What that means is that the brain is the most vascularized organ in the body. "No neuron is more than 40 microns away from a blood vessel," Alan Palmer, co-founder of CNS research firm Pharmidex Inc., told attendees of a Neuroscience 2007 satellite symposium titled, "Passport to the Brain: The Delivery To and Assessment of Potential Therapeutics into the CNS."

But neurons also are trying to keep much of the contents of those same blood vessels at arm's length. "The brain needs a very stable environment to function," as well as protection from toxins and infectious agents, David Begley of King's College London told the audience. And it gets it by means of the blood-brain barrier - actually, Begley said, a set of three barriers in he microvasculature, the cerebrospinal-fluid producing cells of the choroid plexus, and the middle meningeal layer.

The details vary, but each of the three barriers is characterized by tight junctions between cells that make it difficult for many chemicals to pass. And that's where the trouble for drug developers comes in. The barrier combines with the sheer complexity of the brain to turn central nervous system disorders into a major unmet medical need.

At the symposium, researchers spoke about what basic research needs to be done to the blood-brain barrier, as well as assays to predict which compounds will make it across, and a novel delivery method that appears to be able to get brain cancer drugs where they belong.

Begley enumerated the ways in which the blood-brain barrier can be breached by both small and large molecules, including diffusion, transporters, endocytosis, and even cell migration. "The blood-brain barrier is not a brick wall," he told the audience.

Mohammad Alavijeh, co-founder and managing director of Pharmidex, spoke on assaying how well compounds cross that nonbrick wall. Pharmidex specializes in preclinical research on whether compounds are able to pass the blood-brain barrier, using methods from in silico to in vivo. While the majority of clients the company works on are trying to get drugs into the brain, there are also some that are trying to keep them out. "Our very first client . . . was developing antibiotics and wanted them to be unable to breach the blood-brain-barrier," Alavijeh told BioWorld Today.

At the symposium, Alavijeh gave an overview of critical parameters that predict how well a drug will be able to cross, as well as assays his company uses to test how well compounds penetrate. As ever, trick is in balancing speed and accuracy. While Pharmidex can scan up to 100,000 compounds a day in silico, slower in vivo models "give some of the most reliable measures of blood-brain-barrier permeability."

Once drugs have crossed, their availability depends both on whether they bind to proteins in the interstitial space and how tightly they bind. Alavijeh stressed that the critical parameter that determines whether a drug will be able to cross the blood-brain barrier is its concentration and availability in the interstitial fluid, which bathes cells.

The symposium ended with a presentation by Peter Hoffmann, vice president of new technology development at Cambridge, Mass.-based biotech Genzyme Inc., on oligoglycerolipids, which is licensed under the name LipoBridge. Oligoglycerolipids work by briefly opening up tight junctions and allowing compounds that normally would remain excluded to pass through the blood-brain barrier. The same effect can be achieved, in much more brute-force fashion, by using the sugar mannitol, which essentially shrinks the cells and opens up the junctions. But when the method works at all - and Hoffmann noted that its reproducibility, even in the hands of experienced practitioners, is far from stellar - in a sense, it works too well. Mannitol keeps tight junctions open for a minimum of hours, which allows toxins and infectious agents to hitch a ride on the method.

Genzyme developed oligoglycerolipids after several thousand compounds were screened for their ability to enhance blood-brain barrier penetration for molecules that usually are excluded.

Hoffmann said that while the blood-brain barrier usually excludes most compounds larger than 500 daltons, oligoglycerolipids are able to help out compounds of a molecular weight of up to 150,000 daltons, including "typical biotech drugs" such as therapeutic proteins.

Hoffmann presented animal data showing that oligoglycerolipids can improve the long-term response to chemotherapy in rats with experimental Glioblastoma. Collaborating scientists compared no treatment to either chemotherapy alone or chemotherapy delivered with oligoglycerolipids.

While the chemotherapy itself extended lifespan, the extension was similar to many chemotherapy successes. An impressive-sounding survival advantage of more than 50 percent translated into a mere 12 extra days for the rodents receiving chemotherapy alone. In conjunction with oligoglycerolipids, though, the researchers saw long-term survival of more than 40 percent after 90 days, which was as long as the researchers followed them.

The conference ended Wednesday.