Introducing medicine into the bloodstream is generally a very efficient method of distribution, except for the brain. When it comes to the physiology of the vascular system (arteries, veins, capillaries), the brain is different. In the brain, especially for the millions of capillaries, the cells that build their walls form what is technically called the hematoencephalic barrier, better and more easily known as the blood-brain barrier. The blood-brain barrier prevents most bacteria and many toxins (poisons) from entering the cells of the brain through the bloodstream. Meanwhile it permits the relatively free exchange of things needed for metabolism such as oxygen, carbon dioxide, sugars and certain proteins such as hormones. Much to the frustration of medical research, the blood-brain barrier also blocks most forms of medication.
Scientists have been trying to find ways of crossing the blood-brain barrier for at least a century – without a great deal of success. The barrier is ‘porous,’ as it must be to do the job of carrying life-sustaining substances to and from the cells of the brain; but it is very selective about the size and type of molecules it permits to cross the barrier. This selection takes place in the membrane of the blood vessels, where the chemical and physical configuration of proteins blocks or permits passage of molecules. In general there are three main approaches to getting medicine across this barrier: Piggybacking on molecules known to be able to cross the barrier, using nanoparticles small enough to ‘slip through’ the barrier and using chemical stimulators to alter the protein configuration in the barrier (something like opening a gateway). The latest effort, which counts as a success, by a research team at Cornell University (Ithaca, New York, USA) and published in the Journal of Neuroscience [14 September 2011, paywalled, Adenosine Receptor Signaling Modulates Permeability of the Blood–Brain Barrier] uses the last approach.
The research built upon the knowledge that the blood-brain barrier contains adenosine receptors, molecules of adenosine (adenine plus a sugar) that match configuration (receive) certain other molecules of adenosine. For this research, the ‘trigger’ for the receptor is NECA (an adenosine protein). When it binds (or docks) with the adenosine receptor, a path is opened in the blood-brain barrier big enough to transfer larger molecules. In this case, the researchers were successful in transporting macromolecules (e.g. big) such as antibodies (an anti-beta amyloid) and dextrans (a large glucose molecule) across the barrier. Using a similar commercial adenosine compound, Lexiscan, the same effect was achieved with a window of effectiveness of about three hours.
The anti-beta amyloid antibody is one of the medications used to treat Alzheimer’s disease, which immediately illustrates the potential benefit of being able to artificially stimulate transportation of molecules across the blood-brain barrier. The approach of this research has several very important potential benefits: It can, to a certain extent, be controlled in duration, turning the effect on an off. Unlike the piggybacking technique, this approach does not lose drug efficiency, nor does it have the problem of semi-permanent concentrations of the nanoparticle technique.
As promising as the adenosine approach may be, caveats are important: The research was conducted with mice. Although adenosine receptors are also found in human brain capillaries, there is no guarantee that they will respond in identical ways. This is indicative of the probable years of testing and clinical trials that lay ahead before this approach is ready for common applications. On the other hand, a company has already been formed, Adenios, Inc. to handle the patents and trials involved in drug testing – that is usually a solid indicator of probable success. If it works, the adenosine approach may make it finally possible to deliver the complex drugs used to fight Alzheimer’s disease, Parkinson’s disease and many other difficult to treat illnesses of the brain.