What are the factors controlling permeability of the blood brain barrier?

October 12, 2025 •

2 min read

The blood-brain barrier (BBB) is a highly selective semi-permeable membrane that protects the central nervous system, and approximately 98% of all small-molecule drugs fail to cross it. Understanding what are the factors controlling permeability of the blood brain barrier is crucial for developing effective medications for neurological disorders.

Quick Summary

The blood-brain barrier's permeability is controlled by physical tight junctions, specific transport systems, and active efflux pumps. Factors like inflammation, age, and disease can alter its integrity, impacting molecular passage and drug delivery to the brain.

Key Points

Tight Junctions are Key: The physical barrier function of the BBB is primarily controlled by the extensive tight junctions sealing the endothelial cells of brain capillaries.
Transporters Regulate Traffic: Specific carrier-mediated and receptor-mediated transporters facilitate the controlled influx of essential nutrients, while efflux pumps actively remove waste and many drugs.
Physicochemical Properties Influence Passive Diffusion: Small, lipophilic molecules with low hydrogen bonding potential are most likely to cross the BBB via passive diffusion.
Inflammation and Stress Increase Permeability: Systemic or neuroinflammation and oxidative stress can disrupt the BBB by degrading tight junction proteins and stimulating cell adhesion molecules.
Aging and Disease Cause Breakdown: Natural aging and various neurological diseases, including Alzheimer's and stroke, are associated with a breakdown of BBB integrity.
The Neurovascular Unit is a Team Effort: The interaction between endothelial cells, pericytes, and astrocytes within the neurovascular unit is essential for maintaining BBB function.
Efflux Pumps are a Major Obstacle for Drugs: Active efflux transporters, particularly P-glycoprotein, pose a significant challenge for delivering many therapeutics to the brain by pumping them back into the bloodstream.

The Neurovascular Unit: A Complex Gatekeeper

The permeability of the blood-brain barrier (BBB) is a dynamic property regulated by the neurovascular unit (NVU), which consists of brain microvascular endothelial cells (BMECs), pericytes, astrocytes, and the extracellular matrix. This unit forms a restrictive interface that allows essential nutrients into the brain while blocking harmful substances.

Cellular Components and Structural Integrity

Endothelial Cells and Tight Junctions: Cerebral microvascular endothelial cells are tightly connected by tight junctions (TJs) and adherens junctions, which prevent water-soluble molecules and ions from passing between the cells. Proteins like claudin-5 and occludin are important for maintaining this barrier.
Pericytes: Located in the capillary basement membrane, pericytes help maintain BBB integrity by stabilizing TJs and regulating blood flow. Their dysfunction can increase permeability.
Astrocytes: The end-feet of astrocytes surround capillaries and contribute to TJ barrier maintenance through signaling molecules. They also manage water and ion balance.
Basement Membrane and Extracellular Matrix (ECM): This layer around ECs and pericytes provides support and acts as a barrier to cell infiltration. Its components, such as laminin, can be degraded in disease.

Transport Systems and Molecular Characteristics

Beyond the physical barrier, the BBB controls permeability through specific transport systems and is influenced by the physicochemical properties of molecules.

Active Transport and Efflux Pumps

Several transport systems regulate substance movement across the BBB:

Carrier-Mediated Transport (CMT): Solute carriers (SLCs) transport nutrients like glucose and amino acids into the brain. This selective process can be used for drug delivery.
Receptor-Mediated Transcytosis (RMT): Receptors on the cell surface bind ligands and transport large molecules like insulin and transferrin across the endothelial cells in vesicles.
Active Efflux Pumps: ABC transporters like P-glycoprotein (P-gp), MRPs, and BCRP actively pump various molecules, including many drugs, out of the brain endothelial cells. This is a major challenge for brain drug delivery.

Physicochemical Properties

A molecule's ability to cross the BBB by passive diffusion depends on:

Lipophilicity: Lipid-soluble substances can diffuse through the endothelial cell membrane. Higher lipophilicity (measured by logP) generally means better passive diffusion.
Molecular Weight (MW): Molecules under 400-500 Da generally cross the BBB more easily by passive diffusion.
Hydrogen Bonding Potential: Fewer hydrogen bonds can facilitate passage through the lipid membrane.

Influences from Disease and Environment

The BBB's permeability can be altered by various conditions. Inflammatory mediators and reactive oxygen species can damage endothelial cells and tight junctions, increasing permeability. Conditions like Alzheimer's, stroke, and brain tumors are associated with BBB changes. For a detailed comparison of transport mechanisms and their effect on BBB permeability, refer to {Link: Drug Permeability PMC https://pmc.ncbi.nlm.nih.gov/articles/PMC10465108/}.

Conclusion

The permeability of the blood-brain barrier is controlled by its physical structure, specifically endothelial tight junctions supported by the neurovascular unit, alongside specific molecular transport systems and efflux pumps. The physicochemical properties of substances also play a role in their ability to cross. Aging, inflammation, and diseases can disrupt BBB integrity. A thorough understanding of these factors is vital for developing brain-targeting drugs and understanding neurological disorders.

Frequently Asked Questions

Tight junctions are protein complexes that tightly seal the gaps between endothelial cells in brain capillaries, forming a physical barrier that prevents the paracellular diffusion of most water-soluble molecules and ions.

Efflux pumps are ATP-dependent transporters that actively pump a wide variety of molecules, including many therapeutic drugs, out of the endothelial cells and back into the bloodstream. This significantly restricts the entry of these substances into the central nervous system.

Astrocytes, a type of glial cell, extend end-feet that ensheath brain capillaries. They secrete signaling molecules that promote the integrity of endothelial tight junctions and also help regulate ion and water homeostasis, contributing to overall BBB stability.

Inflammation, whether systemic or local to the brain, can increase BBB permeability by releasing cytokines and other inflammatory mediators. These molecules can lead to the degradation and rearrangement of tight junction proteins, creating a leaky barrier.

Lipophilicity, or lipid solubility, is a critical physicochemical property for molecules crossing the BBB via passive diffusion. Highly lipophilic substances can dissolve and pass directly through the lipid membranes of the endothelial cells.

Yes, studies show a natural decline and breakdown of BBB function with age, even in healthy individuals. This is associated with factors like increased inflammation, oxidative stress, and changes in tight junction proteins.

In general, the BBB is more permeable to smaller molecules. A molecular weight threshold of around 400-500 Da is often cited for efficient passive diffusion, with larger molecules typically unable to cross without a specific transport mechanism.