The Blood Brain Barrier

You may have heard of "antisense" technology, that so-called ultimate magic bullet of genetic science that promises to bind to disease-causing strands of messenger RNA and stop them dead in their tracks. Try to imagine antisense turned loose inside your skull, and now imagine kissing your depression goodbye forever.

The catch? There are probably many, but the most obvious one is that any drug which targets any part of the brain must first cross the blood brain barrier (BBB). The name conjures up a kind of cross between the Berlin Wall and a coffee filter, but in fact refers to nearly 400 miles of narrow capillaries throughout the brain, all filled with tightly-packed endothelial cells that are exceedingly selective in what gets through. Endothelial cells are also present in capillaries in the body, but the spacing there poses no difficulty.

The BBB is to protecting the brain internally as the skull is to protecting it externally. The problem is the BBB does not differentiate what it keeps out. Life-saving chemicals, if they happen to be the wrong chemicals, simply won't get through. With very few exceptions, only small molecules soluble in fat clear the barrier. Alcohol, caffeine, and nicotine - all meeting this criteria - have a free pass. So do antidepressants. The problem is, according to William Pardridge MD of UCLA writing in the Jan Archives of Neurology, "small molecules are largely palliative medicines with often unfavorable safety profiles." There are no chronic diseases, other than infectious diseases, that are cured by small-molecule drug therapy.

Large-molecule drugs have the potential to cure patients with neurological disorders, he notes, but none of them can cross the blood brain barrier. The following paragraph is worth quoting in full:

"Despite the importance of the BBB to neuropathic agents, this area is underdeveloped in the neurosciences. To my knowledge, no pharmaceutical company in the world has a BBB drug delivery program! It is not unusual for an entire conference to be convened on a given neurologic disorder (eg brain tumors), with no discussion of targeting drugs through the BBB."

The blood brain barrier makes certain exceptions for allowing passage to large molecules and water-soluble molecules, and exploiting these exceptions is the key to developing new classes of drugs. One binding and transport system in the BBB, for example, permits water-soluble glucose into the brain and another mediates the bidirectional movement of large molecule peptides. According to Dr Partridge: "Based on the knowledge that these endogenous transport systems exist, drugs may be reformulated to enable transport into the brain via the endogenous BBB transporters."

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