Bloodbrain barrier

The blood–brain barrier (BBB) is a highly selective, semipermeable barrier formed by specialised endothelial cells that separates the circulating blood from the central nervous system. Its primary function is to regulate the movement of solutes, nutrients, and signalling molecules between the bloodstream and brain tissue, thereby maintaining a stable environment essential for neural activity. The BBB prevents harmful substances, pathogens, and most large or hydrophilic molecules from entering the brain while allowing the controlled passage of oxygen, carbon dioxide, hormones, and other small, non-polar molecules.

Structure

The BBB is established by the unique characteristics of brain capillary endothelial cells. These cells are joined by continuous tight junctions, which restrict paracellular movement. Tight junction proteins include occludin, claudins, and junctional adhesion molecules, supported by intracellular scaffold proteins such as ZO-1. These molecular assemblies seal the capillary wall and ensure minimal leakage.
Surrounding the endothelial layer are pericytes, embedded within the basement membrane, which help regulate vascular stability, permeability, and growth. Encasing the vessel exterior are astrocytic endfeet (glia limitans), which support endothelial function and integrate vascular signals with neuronal circuits.
The BBB differs from other protective interfaces, such as the choroid plexus and blood–retinal barrier, which have distinct cellular structures and transport roles. Certain brain regions, including the circumventricular organs, naturally lack a fully developed barrier to permit direct monitoring of blood composition.

Development

The barrier is functional at birth. Transporters and protective mechanisms are active in embryonic endothelium, enabling neonatal brain tissue to regulate solute entry similarly to adult tissue.

Function

The BBB’s principal role is to maintain the brain’s internal environment by preventing fluctuations in plasma composition from affecting neural activity. It blocks most toxins, pathogens, and peripheral immune components such as antibodies and circulating immune cells. Essential nutrients and signalling molecules cross via dedicated transport mechanisms, including:

• Carrier-mediated systems for glucose and amino acids
• Ion channels and pumps for maintaining electrochemical gradients
• Receptor-mediated transcytosis for selected peptides and proteins

Because only a narrow range of substances can cross spontaneously, many systemic drugs are unable to reach therapeutic concentrations within the brain. Consequently, treatment of central nervous system infections or disorders often requires agents capable of crossing the barrier or direct administration into cerebrospinal fluid.

Circumventricular organs

Circumventricular organs (CVOs) are specialised brain regions with naturally permeable capillaries. Located near the third and fourth ventricles, they enable rapid exchange between blood and neural tissue. These regions include:

• Area postrema
• Subfornical organ
• Vascular organ of the lamina terminalis
• Median eminence
• Pineal gland
• Pituitary gland

Some CVOs act as sensory structures, detecting circulating signals, while others are secretory, releasing hormones into the bloodstream. Transitional zones between BBB-protected tissue and CVOs contain hybrid capillaries with intermediate permeability, allowing rapid signal exchange while maintaining local control.

Therapeutic research

The restrictive nature of the BBB presents significant challenges for drug delivery to the brain. Most large molecules and the majority of small-molecule drugs cannot cross the barrier without assistance. Current research explores multiple strategies to overcome this obstacle:

• Temporary disruption of the barrier using osmotic or biochemical methods
• Focused ultrasound, creating localised, reversible openings
• Use of natural transport systems, such as glucose and transferrin receptors
• Inhibition of efflux pumps, which remove therapeutic agents from endothelial cells
• Intranasal delivery, utilising neuronal pathways connected to the nasal cavity
• Nanoparticle-based systems, designed to transport drugs across or around the barrier