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What is a Blood-Brain Barrier?

 

It is composed of high-density cells restricting passage of substances from the bloodstream much more than does the endothelial cells in capillaries elsewhere in the body. The brain presents a unique challenge for medical treatment: it is locked away behind an impenetrable layer of tightly packed cells. Although the blood-brain barrier (BBB) prevents harmful chemicals and bacteria from reaching our control center, it also blocks roughly 95 percent of medicine delivered orally or intravenously. As a result, doctors who treat patients with neurodegenerative diseases, such as Parkinson’s, often have to inject drugs directly into the brain, an invasive approach that requires drilling into the skull.

Endothelial cells line the inside of every blood vessel in the body. They form a one-cell-thick later called the endothelium, which is also found on the inner walls of the heart chambers and lymphatic vessels, which carry excess blood plasma around the body. The BBB is a layer of endothelial cells that selectively allow entry of molecules needed for brain function, such as amino acids, oxygen, glucose, and water, while keeping others out.

Cornell researchers report that an FDA-approved drug called Lexiscan activates receptors-called adenosine receptors-that are expressed on these BBB cells. “We can open the BBB for a brief window of time, long enough to deliver therapies to the brain, but not too long so as to harm the brain. We hope in the future, this will be used to treat many types of neurological disorders,” Bynoe’s team was able to deliver chemotherapy drugs into the brains of mice, as well as large molecules, like an antibody that binds to Alzheimer’s disease plaques, according to the paper. The lab also engineered a BBB model using human primary brain endothelial cells. They observed that Lexiscan opened the engineered BBB in a manner similar to its actions in mice. Because Lexiscan is an FDA-approved drug, “the potential for a breakthrough in drug delivery systems for diseases such as Alzheimer’s disease, Parkinson’s disease, autism, brain tumors and chemotherapy-resistant cancers is not far off,” Bynoe said.

Now neuroscientist Viviana Gradinaru and her colleagues at the California Institute of Technology show that a harmless virus can pass through the barricade and deliver treatment throughout the brain. Gradinaru’s team turned to viruses because the infective agents are small and adept at entering cells and hijacking the DNA within. They also have protein shells that can hold beneficial deliveries, such as drugs or genetic therapies. To find a suitable virus to enter the brain, the researchers engineered a strain of an adeno-associated virus into millions of variants with slightly different shell structures. They then injected these variants into a mouse and, after a week, recovered the strains that made it into the brain. A virus named AAV-PHP. B most reliably crossed the barrier. Next the team tested to see if AAV-PHP. B could work as a potential vector for gene therapy, a technique that treats diseases by introducing new genes into cells or by replacing or inactivating genes already there. The scientists injected the virus into the bloodstream of a mouse. In this case, the virus was carrying genes that encoded green fluorescent proteins. So if the virus made it to the brain and the new DNA was incorporated in neurons, the success rate could be tracked via a green glow on dissection. Indeed, the researchers observed that the virus infiltrated most brain cells and that the glowing effects lasted as long as one year. The results were recently published in Nature Biotechnology.

In the future, this approach could be used to treat a range of neurological diseases.

“The ability to deliver genes to the brain without invasive methods will be extremely useful as a research tool. It has tremendous potential in the clinic as well,” says Anthony Zador, a neuroscientist who studies brain wiring at Cold Spring Harbor Laboratory.

Gradinaru also thinks the method is a good candidate for targeting areas other than the brain, such as the peripheral nervous system. The sheer number of peripheral nerves has made pain treatment for neuropathy difficult, and a virus could infiltrate them all.

In 1885, Ehrlich injected blue dye into the bloodstream of mice. The dye stained all of the animals’ organs blue- except their brains. In a follow-up experiment in 1913, one of Ehrlich’s students injected the same dye directly into the brains of mice. This time, the brains turned blue, whereas the other organs did not. Although these experiments suggested a physical barrier between the brain and the bloodstream, no such barrier could be detected with the instruments of the time.

It took until the 1960s before scientists were able to catch a glimpse of the actual barrier standing between the rest of the body and the brain. Using a microscope that was roughly 5,000 times more powerful than the one Ehrlich used, scientists could see the detailed anatomy of the network of blood vessels in the brain comprising what is now known as the blood-brain barrier.

Similar to all other blood vessels in the body, scientists learned that the brain’s blood vessels are lined with endothelial cells, which serve as an interface between circulating blood and the vessel wall. However, unlike other blood vessels in the body, the endothelial cells in the brain are tightly wedged together, creating a nearly impermeable boundary between the brain and bloodstream.

The blood-brain barrier helps block harmful substances, such as toxins and bacteria from entering the brain. But, scientists knew that the brain also depends upon the delivery of hormones and key nutrients, including glucose and several amino acids, from other organs of the body.

Through extensive study, scientists have found that compounds that are very small and/or fat-soluble, including antidepressants, anti-anxiety medications, alcohol, cocaine, and many hormones are able to slip through the endothelial cells that make up the blood-brain barrier without much effort. In contrast, larger molecules, such as glucose or insulin, must be ferried across by proteins. These transporter proteins, located in the brain’s blood vessel walls, selectively snag and pull the desired molecules from the blood into the brain.

Cells within and on either side of the blood-brain barrier are in constant communication about which molecules to let through and when. For instance, if the nerve cells in a region of the brain are working particularly hard, they will signal to the blood vessels to dilate, allowing cell-powering nutrients to quickly travel from the blood to the nerve cells in need.

When the blood-brain barrier breaks down, as is the case in some brain cancers and brain infections or when tiny ruptures to blood vessels occur, some substances that are normally kept out of the brain gain entry and cause problems for the brain.

Some evidence suggests the weakening of the blood-brain barrier may even precede, accelerate, or contribute to a number of neurodegenerative disorders. For instance, studies suggest a leaky blood-brain barrier allows too many white blood cells into the brains of people with multiple sclerosis (MS). With access to the brain, these cells attack myelin, the insulating coating between nerve cells, leading to the disease’s devastating symptoms.

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