Histological structure of the BBB
The barrier is a multilayered structure in which each element performs its filtration function.
- Capillary endothelial cells of the brain. Unlike peripheral vessels, there are no intercellular clefts between these cells. The cells are connected by tight junctions — specific proteins that block paracellular (intercellular) transport. In addition, pinocytosis (fluid uptake) is practically absent in the brain endothelium.
- Basal lamina.
- Pericytes (pericytae).
- Astrocytes (astrocyti) — glial cells whose processes surround capillaries from the outside.
Mechanisms of drug permeability
The ability of a drug to penetrate the brain depends directly on its chemical structure.
- Lipophilic (non-polar) substances can cross endothelial cell membranes via passive diffusion.
- Hydrophilic (polar) substances cannot pass through tight junctions. Specific pathways are provided for them: receptor-mediated endocytosis (how insulin penetrates) or transport proteins (for example, for levodopa).
The BBB is not only a physical wall, but also an active transport system. It contains efflux transporters, the most important of which is P-glycoprotein (as well as ATP-dependent proteins and organic anion SLC transporters). Their task is the active removal (efflux) of xenobiotics and lipophilic drugs from brain tissue back into the blood.
Clinical example: The prokinetic Metoclopramidum penetrates the CNS and causes extrapyramidal symptoms. Its analog Domperidonum is a substrate for P-glycoprotein, is actively pumped out of the brain, and acts only peripherally without causing central side effects. Similarly, the second-generation antihistamine Fexofenadinum is removed by transport proteins, which is why it lacks sedative effects.
Factors altering permeability
BBB permeability can change. This is promoted by:
- Physical factors: elevated blood pressure or plasma osmotic pressure, exposure to radiation and microwaves.
- Biochemical mediators: histamine (Histaminum) and bradykinin.
- Pathological conditions: traumatic brain injury, ischemia, neurodegenerative diseases (Alzheimer's disease, multiple sclerosis), and inflammation.
In clinical practice, these changes are often used to advantage. For example, in bacterial meningitis, the barrier allows even hydrophilic molecules to pass, which makes it possible to treat the patient with intravenous benzylpenicillin (Benzylpenicillinum). In oncology, osmotic opening of the BBB is used: administration of Mannitolum increases osmotic pressure, disrupts the structure of endothelial tight junctions, and enhances paracellular transport, clearing the way for chemotherapy drugs.
Strategies to overcome the BBB
The challenge in treating many CNS diseases is that active efflux reduces drug concentrations in the brain below therapeutic levels. Pharmacology uses several ways to bypass this:
- Use of prodrugs. An inactive substance is administered, which is activated only in the brain. The molecule is modified to increase lipophilicity (e.g., gabapentin) or to bind to carriers (levodopa).
- Inhibition of efflux transporters. Combining a drug with a P-glycoprotein inhibitor. For example, the blocker Verapamil increases the concentration of antifungal agents (itraconazole) or HIV protease inhibitors in the brain.
- Nanotechnology. Drugs are placed inside biodegradable polymer particles (10–1000 nm in size) or conjugated to their surface. This allows the transport of peptides (dalargin), bypassing P-glycoprotein (loperamide), or the delivery of oncological drugs (doxorubicin).
Briefly: answers to topical questions
Which specific transport protein ensures the penetration of levodopa across the blood-brain barrier?
- Aromatic amino acid transporter protein — ensures the transfer of levodopa across the endothelium of the blood-brain barrier due to chemical similarity with endogenous substrates.
- Aromatic amino acid transport system — a specialized mechanism of active transport of levodopa across the blood-brain barrier.
Class and exam questions
Why doesn't domperidone cause central side effects, yet works as an antiemetic?
Domperidone is a substrate of P-glycoprotein and is actively pumped out of the brain tissue. However, it exerts an antiemetic effect because it blocks dopamine D2 receptors in the trigger zone of the vomiting center—an area where the blood-brain barrier is absent.
Why is mannitol used in neurooncology?
Mannitol is used to artificially increase plasma osmotic pressure. This leads to the temporary disruption of tight junctions between endothelial cells, allowing chemotherapy drugs to penetrate the brain via the paracellular (intercellular) pathway.
Why don't second-generation antihistamines cause drowsiness?
Drugs like fexofenadine are substrates of BBB transport proteins. Upon entering the brain tissue, they are immediately removed (effluxed) back into the blood, and therefore do not have time to exert a sedative effect on the CNS.
What else to study on this topic
- Mechanism of receptor-mediated endocytosis across the BBB using insulin as an example
- The role of organic anion SLC transporters in CNS protection
- Features of BBB permeability in demyelinating diseases (multiple sclerosis)
- Prodrug development: chemical modifications for binding to membrane transporters
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