The New York Times - December 30, 1986
Harold M. Schmeck Jr.

Many substances that circulate in the blood hardly enter the brain at all. Some chemicals in the brain will not diffuse outward into the general circulation.

This strange selectivity is vital to the brain's proper function. But recently scientists have learned much about how to manipulate it to help the whole body fight disease.

The selectivity is achieved by the blood-brain barrier, a physical and chemical entity that keeps the brain stable in a body whose blood chemistry can have drastic momentary ups and downs. The barrier is a vital defense, but it is also a serious problem in treating diseases such as AIDS, some cancers and other diseases that invade the brain. Important drugs that could be useful against disease in the brain do not easily penetrate the barrier. Other diseases that might be better understood and treated through study of the blood-brain barrier include Alzheimer's disease and multiple sclerosis.

For years scientists virtually ignored the blood-brain barrier because there seemed to be no way of dealing with it. Today it is a subject of intense research. Specialists see it as a vital point of attack against deadly diseases and as a source of clues to better understanding of the the most complex single thing that has ever existed on earth - the human brain.

"Our focus really is to understand how the system works," said Dr. A. Lorris Betz of University of Michigan Medical Center, speaking of the barrier. "The whole thing is much more complicated than people had originally imagined."

The barrier is actually a feature of the physical structure and the chemistry of the brain's capillaries, the tiny blood vessels that supply blood to the brain tissue. Scientists have found that these capillaries are different from those in the rest of the body. The outer covering of the brain capillaries consists of surface endothelial cells that are joined to each other with impermeable junctions. The cells of capillaries elsewhere in the body are much less tightly joined. Furthermore, ordinary capillaries have apertures more or less like pores through which most chemicals can pass. Brain capilaries have far fewer of these.

In addition, specialists understand today that substances that dissolve easily in lipids, fatty substances, pass easily through the walls of these capillaries. Substances that dissolve in water are kept out unless they have special help.

Nicotine and alcohol dissolve readily in lipids. They pass through the blood brain barrier so fast that their effects on the brain can begin within seconds of their appearance in the blood. Nicotine's stimulant effects, for example, can appear in just the few seconds it takes blood to flow from the lungs to the brain.

The barrier is a vital source of stability as well as defense. After an ordinary meal, for example, blood concentrations of some important chemicals can rise sharply. If those changes affected the brain too, chaos could result. The barrier protects the brain against such fluctuations and may be why it evolved. All mammals and other vertebrates have a blood-brain barrier. Their lives depend on brains that function reliably no matter what the environment does. Simpler animals in which the brain is less crucial, lack the barrier.

The protection is not limited to food intake. The person who plunges into cold water gets a sudden burst of the stress hormone epinephrine coursing through the blood in response to the crisis. If that same excess got into the brain there could be disastrous effects on its function. But the barrier prevents it.

Unfortunately the barrier also makes the brain a safe haven for cancer cells that can multiply there and kill a patient no matter what cancer-killing drugs are circulating through the rest of the body.

Some viruses, including that of AIDS, seem to have devised stratagems for penetrating the barrier. Experts say progress against acquired immune deficiency syndrome in particular will be seriously handicapped unless anti-virus drugs can be developed that pass through the barrier. But changes in drug chemistry that might help a substance slip through the barrier may destroy its effectiveness.

Some biotechnology companies are attacking this problem in various ways. A Florida company, Pharmatec, using ideas put forward by Dr. Nicholas S. Bodor of University of Florida, Gainesville, is linking potential drugs to fat soluble molecules in the hope of helping them through the barrier. The virtues of all novel approaches to the blood-brain barrier, including this one, are subjects of debate among scientists.

Other research workers are trying to breach the barrier itself temporarily. A seemingly moderate treatment, infusion of a heavy dose of a special sugar into an artery leading to the brain, can open the barrier briefly so that otherwise prohibited substances can enter. This strategy is credited to Dr. Edward A. Neuwelt of Oregon Health Sciences University and Dr. Stanley I. Rapoport of the National Institute of Aging, a unit of the National Institutes of Health in Bethesda, Md. They injected heavy doses of arabinose into the carotid arteries of laboratory animals and found that the barrier was relaxed on the side of the brain fed by that artery. The barrier stayed intact on the other side, showing that the effect was produced by the arabinose, a sugar that is not metabolized by the body and will not itself cross the barrier.

Recently Dr. Neuwelt tried this strategy in conjunction with drug treatment of cancer patients.

"His recent work suggests that chemotherapeutic drugs given in this way may contribute to regression or disappearance of the tumor," two researchers said in a recent scientific article.

In the past, the blood-brain barrier was little discussed and seldom a subject of research, said Dr. William M. Pardridge of University of California at Los Angeles. The barrier was thought to be immutable and static and there wasn't much to be done about it.

In recent years that simple and pessimistic idea has been largely displaced, he said. Research has shown that the barrier is complex, dynamic and potentially subject to manipulation.

Recently scientists have learned how their increasing ability to manipulate the barrier may help cope with diseases that are today incurable.

AIDS, some cancers, Alzheimer's disease and some problems of diabetics are examples. Dr. Pardridge said a key factor in Alzheimer's appears to be the accumulation in the brain tissues of tangled protein strands called amyloid.

Amyloid presumably would have no chance of crossing the blood-brain barrier itself. But there is strong evidence that a smaller substance, a short string of amino acids named the A-4 peptide is important in forming the amyloid tangles. It is still unknown whether the peptide forms in the brain or blood and crosses the barrier to get inside the brain.

The A-4 peptide was discovered about two years ago by Dr. George Glenner of University of California in San Diego. Preventing the A-4 peptide from crossing the blood-brain barrier might conceivably help prevent the disease. The theory that this approach might help prevent Alzheimer's disease is not yet even close to proof, but Dr. Pardridge noted that it illustrates the importance of studying the barrier.

There are also other urgent medical reasons to open doors selectively into the brain. Many leukemia patients have died because some drugs that combat the disease effectively in other parts of the body will not cross the blood-brain barrier. The disease smoulders in the sanctuary of the brain and ultimately kills the patient.

Drugs that will not pursue the AIDS virus through the barrier have little hope of curing that deadly disease.

The existence of the blood-brain barrier has been known for almost 100 years, until recently it has been totally mysterious, little more than a figure of speech to explain some of its effects.

Less than a generation ago, medical students were taught that the blood-brain barrier was an absolute, if mysterious, bar. Most of what was "understood" about it was wrong, but the misconceptrtions seemed to discourage scientists from studying it.

In spite of recent evidence, Dr. Pardridge said, some major drug companies still almost ignore it on the grounds that there is nothing there worth exploiting.

The scientist disagrees with this most emphatically. A decade or so from now, he predicted, most drugs will be based on peptides, small strings of amino acids, designed either to cross the blood-brain barrier or to be incapable of doing so depending on the purpose of the drug.

Today it is known substances that can dissolve in oils and fats pass through the barrier more readily than substances that dissolve in water. This discovery explains why penicillin, water soluble and earliest of the antibiotic drugs, will not pass through the blood-brain barrier while fat soluble chloramphenicol, another early anti-bacterial drug, will do so.

When the drugs were first discovered no one knew why their ability to penetrate the brain differed so greatly.

Today the known chemistry and physical structure of the barrier are suggesting to medical scientists new strategies to make the brain accessible to lifesaving medical treatment and to help protect it from other things.

The special characteristics of the brain's capillaries appear to form during embryonic life at the orders of the developing brain itself. It appears that the developing brain sends out chemical signals telling the capillaries that will supply it with blood to form tight junctions and to make only a few other apertures where chemicals could pass through. Capillaries elsewhere in the body get different growth signals and therefore develop characteristics that differ somewhat from organ to organ according to the tissues' special needs.

Because portions of the brain cells called astrocytes seem to surround the brain capilaries it was once thought that they constituted the blood-brain barrier. Today, according to Dr. William H. Oldendorf, of the University of California at Los Angeles, it is believed that the astrocytes secrete a still unidentified chemical that makes the brain capillaries grow in the way they do.

Some chemicals will pass through the barrier because they are soluble in lipids and use this quality to pass though lipid structures in the capilary membranes.

Others pass through because they are capable of attaching, in lock and key fashion, to proteins called transporters, that guide them through the capillary wall as though the transporters were elevators and the chemicals seeking passage were passengers. The transporters are imbedded in the membranes.

Some transporter proteins are shaped more or less like doughnuts.

Substances with special chemical configurations, sizes and characteristics of electrical charge can gain entry through the "holes" in the "doughnuts".

Glucose, a natural form of sugar vital to the brain as an energy source, isone of the important substances that uses a transporter protein to gain entrance to the brain tissues.

The brain needs it urgently and continually, but glucose is soluble in water rather than lipids. Its affinity for one type of transporter protein imbedded in the inner membrane of the capillary gives it prompt entry.

Much still remains to be learned about the nature and function of these protein transporters. The capillary has two membranes separated by cellular substance of the endothelial cells that line the capillaries. A substance in the blood capable of gaining entry through the barrier must fit one of the transporter proteins in a lock and key fashion. Then, in a process still little understood, some chemical change occurs so that the transporter protein brings the substance quickly through the first membrane. Something else, also still largely a subject of research and speculation, then helps the substance through the second membrane and gives it access to the fluid that surrounds the cells of the brain.

The practical consequences of differences in lipid solubility are illustrated by the differences between the brain's reactions to the narcotic drugs morphine and heroin. Morphine is less soluble in lipid than heroin and therefore does not enter the brain as readily. Once inside the brain, heroin undergoes a chemical change that impairs its ability to cross the barrier. In consequence, heroin enters the brain more readily and, once inside, stays there more durably and presumably with greater effects on brain and mind. Drs. Betz and Gary W. Goldstein of

University of Michigan suggested implications of the recent discoveries in an article on the blood-brain barrier in Scientific American.

"Such principles and others suggest that the recent advances in understanding the blood-brain barrier will have important clinical applications in the years to come," they said.

861230
NYT861229