The blood-brain barrier (BBB) is a dynamic and highly selective interface that separates the circulating blood from the brain's extracellular fluid. Its primary role is to maintain the stable microenvironment necessary for proper neuronal function by preventing the entry of pathogens, toxins, and most large or hydrophilic molecules. This same protective function, however, represents a significant hurdle for treating central nervous system (CNS) diseases, as it restricts the entry of approximately 98% of small-molecule drugs and nearly all large-molecule drugs.
Core properties that prevent passage
Several physicochemical properties primarily determine whether a substance can traverse the BBB. Molecules that fail to cross typically possess one or more of these characteristics, preventing passive diffusion across the lipid-rich endothelial cell membranes.
- Large Molecular Size: Molecules with a molecular weight over 400–500 daltons are generally too large to cross the tight junctions between the brain's endothelial cells. The tightly packed nature of these cells effectively eliminates the paracellular pathway used by substances in other parts of the body. This size restriction prevents entry for almost all large biologicals, such as proteins, peptides, and antibodies.
- High Water-Solubility (Hydrophilicity): The endothelial cells forming the BBB have lipid-based cell membranes. These membranes repel water-soluble molecules, making it difficult for them to pass via passive diffusion. A drug's ability to cross by this method decreases exponentially with each hydrogen bond it can form.
- Strong Polarity or Charge: Highly polar or charged molecules struggle to cross the lipid-based barrier. The more polar a substance, the less likely it is to be soluble in the cell membrane and diffuse across. Dopamine is too polar to pass, requiring the use of its precursor, L-Dopa, for Parkinson's treatment.
- Substrates for Efflux Transporters: Brain endothelial cells have ATP-binding cassette (ABC) efflux transporters like P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP). These actively pump substrates from cells back into the bloodstream.
Specific substances that do not cross the blood-brain barrier
Many substances, including large-molecule biologics, some antibiotics like streptomycin, and neurotransmitters such as dopamine, do not cross the BBB effectively. White blood cells also do not easily cross in a healthy state.
Strategies to overcome the blood-brain barrier
The BBB's restrictiveness has spurred research into innovative drug delivery methods. Prodrugs, like L-Dopa for dopamine, modify substances to cross the barrier. The "Trojan Horse" method uses natural transport systems by attaching drugs to molecules like glucose or transferrin. Temporary BBB disruption can be achieved through methods like focused ultrasound with microbubbles or hyperosmotic agents. Nanoparticles can encapsulate drugs to aid passage.
Comparison of substance permeability across the blood-brain barrier
| Feature | Substances that cross the BBB | Substances that do not cross the BBB |
|---|---|---|
| Molecular Size | Small (typically < 400-500 Da) | Large (proteins, antibodies, peptides) |
| Lipid Solubility | High (favors passive diffusion) | High water-solubility (repelled by lipid membrane) |
| Charge/Polarity | Low charge or non-polar | Highly polar or charged (e.g., dopamine, many antibiotics) |
| Transport System | Utilizes carrier-mediated transport (CMT) or lipid diffusion | Actively ejected by efflux transporters (P-gp, MRP) |
| Delivery Examples | Alcohol, caffeine, some anesthetics | Most large biologics, streptomycin, dopamine |
The blood-brain barrier and clinical considerations
The BBB's permeability is clinically significant. Dysfunction in diseases like Alzheimer's or Parkinson's can impact drug delivery. BBB breakdown in stroke might allow drug entry but cause edema. Autoimmune disorders like MS involve compromised BBB integrity, allowing immune cell entry. Factors like genetics, age, and inflammation influence BBB integrity. [A link to further research could be inserted here, for instance, a review on BBB drug delivery from a reputable journal like Nature Reviews Neuroscience if a specific article was identified in the search, e.g., a review cited in or.]
Conclusion
The blood-brain barrier is essential for protection but challenges drug delivery for CNS disorders. Substances that do not cross the BBB are typically large, water-soluble, or highly charged, necessitating innovative delivery methods. Continued research into BBB mechanisms and transport systems is vital for developing effective therapies.
