The Blood-Brain Barrier: Anatomy and Mechanisms of Exclusion
The blood-brain barrier (BBB) is a highly selective, semipermeable membrane that separates the circulating blood from the brain extracellular fluid in the central nervous system (CNS). It is formed by specialized endothelial cells that line the brain's capillaries, which are joined by unique, high-resistance tight junctions. These junctions prevent substances from passively diffusing between the endothelial cells, forcing them to pass directly through the cell membranes. This design is critical for maintaining the brain's stable chemical environment and protecting it from harmful substances.
Beyond this physical barrier, the BBB uses active mechanisms to prevent drug entry:
- Active Efflux Transporters: Pumps like P-glycoprotein (P-gp), BCRP, and MRPs are abundant in BBB endothelial cells. These pumps actively transport a wide range of drugs back into the bloodstream.
- Enzymatic Barriers: The BBB contains enzymes that can break down substances before they enter the brain.
Drug Properties That Prevent Blood-Brain Barrier Crossing
A drug's ability to cross the BBB passively depends on its physicochemical properties. Drugs lacking these properties are typically excluded:
- High Molecular Weight: The BBB is largely impermeable to large molecules, with successful small molecule penetration generally limited to those under 400-500 Da. Large molecules, such as antibodies and peptides, are typically blocked.
- Low Lipid Solubility (Hydrophilicity): The lipid-rich membranes of BBB endothelial cells repel water-soluble substances. Polar or charged molecules, which are highly water-soluble, struggle to cross these membranes.
- High Hydrogen Bonding Potential: A drug's capacity to form hydrogen bonds influences its lipid solubility. Compounds forming many hydrogen bonds are usually water-soluble and have difficulty crossing the BBB.
Examples of Drugs Excluded by the Blood-Brain Barrier
Many drugs are designed to not cross the BBB to minimize CNS side effects:
- Second-Generation Antihistamines: Unlike older antihistamines, newer ones like fexofenadine and loratadine are designed not to enter the CNS, avoiding sedation.
- Large Molecule Biologics: Antibodies and peptides used outside the CNS are generally too large to cross the BBB. Vancomycin, a large antibiotic, also cannot cross, requiring alternative treatments for brain infections.
- Hydrophilic Antibiotics: Many water-soluble antibiotics, including penicillin and vancomycin, poorly penetrate the BBB under normal conditions, posing a challenge for treating brain infections.
- Certain Antihypertensive Drugs: Some ARBs like olmesartan do not easily cross the BBB, unlike others such as telmisartan.
- Neurotransmitters: Dopamine and serotonin do not cross the BBB when given systemically. L-dopa, a precursor that can cross, is used for Parkinson's disease.
Comparison of BBB Penetration: Examples
| Drug Property | Characteristic of a Drug that Cannot Cross BBB | Example | Characteristic of a Drug that Can Cross BBB | Example |
|---|---|---|---|---|
| Molecular Size | High molecular weight (e.g., >500 Da) | Vancomycin | Low molecular weight (e.g., <400 Da) | Ethanol |
| Lipid Solubility | Hydrophilic (water-soluble) | Fexofenadine | Lipophilic (fat-soluble) | Caffeine |
| Charge | Charged (ionized) | Quaternary ammonium compounds | Uncharged (non-ionized) | Most anesthetics |
| Efflux Substrate | A substrate for efflux pumps (e.g., P-gp) | Certain anticancer drugs | Not a substrate for efflux pumps | Levodopa (uses specific carrier) |
Challenges and Future Perspectives for CNS Therapies
The BBB's impermeability is a major obstacle for treating CNS disorders. Researchers are developing strategies to improve drug delivery to the brain: Focused ultrasound with microbubbles may temporarily increase BBB permeability, while nanoparticles and liposomes can encapsulate drugs for better transport. Attaching drugs to molecules that use the BBB's natural transport systems is another approach, as is delivering drugs directly into the cerebrospinal fluid. These methods require further development for safe clinical use.
Conclusion
Drugs that cannot cross the blood-brain barrier are typically large, water-soluble, or charged molecules, or those targeted by efflux pumps. This poses challenges for treating CNS diseases. Research into new delivery methods aims to overcome these limitations. {Link: Wikipedia https://en.wikipedia.org/wiki/Drug_delivery_to_the_brain}
