Blood-brain barrier (BBB)

The blood-brain barrier (BBB) is an important mechanism that the body uses to protect the brain and central nervous system (CNS). Throughout the body, endothelial cells are arranged to allow substances to pass through more easily, which allows the bloodstream to act as an effective transport service for important molecules. However, near the brain, endothelial cells are closely packed. Their placement prevents most particles from passing through the blood and into the brain and CNS.

Certain atoms and molecules, such as oxygen, are capable of crossing the blood-brain barrier. These materials are often necessary for the function of the CNS, and the blood-brain barrier evolved to stop pathogens and toxic substances from passing through the bloodstream and entering the brain. In this way, the blood-brain barrier works to keep the body safe.

However, the blood-brain barrier is sometimes detrimental to a patient’s health. Certain diseases of the brain and CNS are difficult or impossible to treat because the barrier prevents medicine from reaching its intended target. Scientists have researched various therapies that can bypass the blood-brain barrier, including using specially designed nanoparticles, using transport proteins, and using focused ultrasound to temporarily open the barrier.

Background

During the early twentieth century, Paul Ehrlich conducted experiments using the bloodstream, and Edwin Goldmann later expanded on this work with similar dye studies. They injected water-soluble dyes into the peripheral circulation system. These dyes temporarily stained the body, allowing the researchers to verify the exact regions of the body that were accessible through the peripheral circulation system. However, they discovered that the stain was unable to reach the brain or cerebrospinal fluid.

Researchers Ehrlich and Goldmann saw promise in these results and continued experimenting. During follow-up testing, they discovered that if the dye was injected directly into the subarachnoid space, which contained cerebrospinal fluid, it would stain the brain and cerebrospinal fluid. However, the dye was then unable to reach the rest of the body. This showed that certain materials, when injected into the body’s circulatory system, were unable to penetrate the brain. Max Lewandowsky is often credited with coining the term “Blut-Hirn-Schranke,” which translates to blood-brain barrier, in 1900.

In 1942, scientists continued experimenting on the blood-brain barrier. They attempted similar experiments, this time using dyes that were highly lipid-soluble. These tests showed staining in the brain and cerebrospinal fluid, demonstrating that certain materials were able to cross the barrier. Later research showed that the brain contained two separate barrier systems: the blood-brain barrier and the blood–cerebrospinal fluid (CSF) barrier. In the 1960s, electron microscope cytochemical studies discovered the exact mechanisms that allowed the blood-brain barrier to operate. Later studies showed that molecular signaling pathways, such as Wnt/β-catenin signaling, help control the development and maintenance of the blood-brain barrier.

Overview

Endothelial tissue is a thin layer of cells that lines blood vessels throughout the body. In most of the body, the cells that make up endothelial tissue are loosely arranged. This allows substances to pass from the blood to other bodily tissues, which lets the blood serve as a mechanism for transporting important substances. Many important substances that enter the body, such as oxygen, are transported to their destination through the bloodstream. However, in the brain’s capillaries, the endothelial cells are connected tightly to one another and are supported by surrounding cells such as astrocytes and pericytes. This stops certain molecules from crossing through the blood and into the brain. However, some small regions of the brain, such as the area postrema and parts of the hypothalamus, do not have a typical blood-brain barrier. The blood-brain barrier is part of a larger system called the neurovascular unit, which includes endothelial cells, astrocytes, and pericytes that work together to control what enters the brain.

The brain cannot exist in a closed system. It needs certain types of chemicals to function effectively. These essential molecules, including oxygen, are capable of freely passing through the blood-brain barrier. Additionally, fat-soluble substances are often capable of crossing the blood-brain barrier. Common fat-soluble substances that pass into the brain include caffeine and alcohol. Other materials that are necessary for the brain’s function may be transported across the blood-brain barrier with transport proteins.

When functioning correctly, the blood-brain barrier serves as a filter for the brain, keeping foreign materials that enter the bloodstream away from the brain matter. This safeguards the CNS from most forms of infection. The blood-brain barrier also plays a role in controlling immune signals between the brain and the rest of the body. However, it is possible for the blood-brain barrier to become compromised. For example, certain traumatic brain injuries or strokes can cause permanent damage to endothelial tissue, resulting in significant damage to the blood-brain barrier. If the blood-brain barrier is damaged, the brain may become vulnerable to toxic compounds from outside the body. Research shows that reduced function of the blood-brain barrier is an early warning sign that cognitive impairment, such as dementia, may occur in older individuals. Changes in the blood-brain barrier have also been linked to other neurological conditions, including Alzheimer’s disease, amyotrophic lateral sclerosis, and epilepsy.

While the blood-brain barrier does a remarkable job of keeping the brain safe, it sometimes makes it difficult or impossible for doctors to treat patients. For example, sometimes injuries, diseases, or tumors are localized in the brain or the cerebrospinal fluid. If these problems had occurred in other places in the body, doctors might be able to treat them with medication. However, the blood-brain barrier prevents most drugs from passing through to the brain. This can make it difficult for some medicines to reach the brain.

To combat this problem, doctors have researched methods of passing foreign substances through the blood-brain barrier. Some researchers are working to develop transport systems that carry them through the blood-brain barrier. These transport systems require the creation of specialized antibodies that bind to receptors within the endothelial cells. Some of these methods use receptor-mediated transport, in which drugs attach to receptors such as transferrin or insulin receptors to move across the barrier. Other proposals involve temporarily opening the blood-brain barrier to allow medicines to pass through. These might utilize microscopic bubbles and ultrasounds to temporarily create openings in the barrier. However, many researchers worry that the medical consequences of temporarily opening the blood-brain barrier have not been thoroughly explored. They worry that such practices might place patients at risk of infections or damage the blood-brain barrier. Focused ultrasound is a technique that involves using focused ultrasound combined with microbubbles to temporarily open the blood-brain barrier, and chemical modulation has also been used to disrupt the blood-brain barrier.

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