Blood–brain barrier

The blood–brain barrier, or BBB, is a highly selective semipermeable border. It regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system. This system is vital because it protects the brain from harmful or unwanted substances found in the blood. By acting as a filter, the BBB ensures the brain maintains a stable environment. Without this protection, the brain could be damaged by many things circulating in the body.

This barrier is formed by several specialized components working in coordination. The primary structure consists of endothelial cells that make up the capillary walls. These cells are joined together by tight junctions. These junctions are composed of transmembrane proteins such as occludin, claudins, and junctional adhesion molecules. To stabilize these junctions, the cells use scaffolding proteins like tight junction protein 1 (ZO1). Additionally, pericytes are embedded within the capillary basement membrane. Finally, astrocyte cell projections, known as astrocytic feet, wrap around the endothelial cells to provide biochemical support.

The BBB uses different methods to move substances into the brain. It allows small, non-polar molecules to pass through via passive diffusion. This includes essential gases like oxygen and carbon dioxide, as well as certain hormones. For more complex needs, the barrier uses active transport. Specific transport proteins move metabolic products, such as glucose and amino acids, across the border. These nutrients are crucial for neural function. However, the barrier also restricts the passage of many things. It blocks large or hydrophilic molecules and most pathogens. It even prevents peripheral immune factors, such as antibodies and immune cells, from entering. This insulation protects the brain from damage caused by peripheral immune events.

While most of the brain is highly protected, some areas are different. These are called circumventricular organs, or CVOs. These structures, such as the area postrema and the pineal gland, have highly permeable capillaries. Unlike the rest of the brain, these capillaries allow for rapid detection of signals in the blood. CVOs act as points of bidirectional communication. Sensory CVOs allow the brain to detect circulating signals. Secretory CVOs help transport brain-derived signals into the blood. There are also specialized hybrid capillary zones. These zones act as rapid transit regions between the protected brain tissue and the open CVOs.

Scientists have been uncovering the secrets of this barrier for over a century. In 1898, researchers noticed that certain bile salts did not change animal behavior after injection. This suggested the salts could not reach the brain. By 1900, Max Lewandowsky may have first used the term "blood–brain barrier." However, some believe the Russian scientist Lina Stern actually created the term. In 1913, Edwin Goldmann provided crucial evidence for the barrier's existence. He injected dye directly into the cerebrospinal fluid of animal brains. He found the brain became dyed, while the rest of the body did not. This proved there was a clear compartmentalization between the blood and the brain.

The strength of the BBB creates significant challenges for modern medicine. The barrier excludes 100% of large-molecule neurotherapeutics from the brain. It also blocks more than 98% of all small-molecule drugs. This makes delivering medicine to specific brain regions a major hurdle for treating disorders. Researchers are looking for ways to bypass this. Some methods involve disrupting the barrier using ultrasound or chemical substances. Others try to use the brain's own transport systems, such as insulin carriers. Scientists are even studying nanotechnology to help move drugs across. Another non-invasive method is intranasal administration, which uses the olfactory or trigeminal nerves to reach the brain.

Maintaining the integrity of the BBB is essential for health. The barrier is functional by the time a person is born. However, it can be damaged by various neurological and systemic diseases. Conditions like Alzheimer's disease, epilepsy, and ischemic stroke are linked to BBB damage. Even liver failure can affect its function. When the barrier is compromised, it may allow proinflammatory factors to enter the brain. This can lead to metabolic dysfunction. Emerging evidence also suggests that a healthy gut microbiome is necessary to maintain the barrier during development and aging. Understanding these connections is key to treating brain diseases.