The brain is protected by a highly selective, semipermeable border called the blood-brain barrier (BBB). This structure consists of endothelial cells lining the brain’s capillaries, which are held together by protein complexes known as tight junctions. These junctions restrict the passage of most substances from the blood into the central nervous system. This protects the brain from pathogens and toxins, maintaining the stable environment required for neural function.
Mechanisms of Transport Across the Barrier
The ability of a substance to cross the blood-brain barrier is dictated by its chemical properties. One mechanism is passive diffusion, where small, fat-soluble (lipophilic) molecules move directly through the endothelial cell membranes. This process favors molecules with a molecular weight of less than 400 Daltons.
Larger or water-soluble (hydrophilic) molecules require specific transport systems. Carrier-mediated transport uses proteins to carry molecules like glucose and amino acids across the barrier. A similar method, receptor-mediated transcytosis, uses surface receptors to bind to larger molecules like insulin and transport them across in small vesicles.
Some systems use energy (ATP) to actively move substances against their concentration gradient. The barrier also has efflux pumps, which are transport proteins that actively remove foreign substances or drugs that have entered the brain. The well-known P-glycoprotein pump expels a wide range of molecules, presenting a challenge for delivering therapeutic drugs.
Substances That Natively Cross the Barrier
Several substances naturally pass through a healthy blood-brain barrier. Gases like oxygen and carbon dioxide diffuse freely across the barrier. Water also moves across with relative ease through osmosis to maintain fluid balance.
The brain’s high energy demand is met by a constant supply of glucose, its primary fuel. Glucose is ferried across by a specific carrier protein known as GLUT1. Similarly, essential amino acids, which are building blocks for proteins and neurotransmitters, use dedicated transporters like the L-type amino acid transporter (LAT1) to enter the brain.
Beyond nutrients, many other small, lipophilic molecules can penetrate the BBB. This category includes steroid hormones, which regulate various physiological functions. It also includes psychoactive substances like ethanol, caffeine, and nicotine, which readily cross into the brain and cause rapid effects on mood and alertness.
When the Barrier Is Compromised
The blood-brain barrier can be compromised by various medical conditions, causing it to become “leaky” and lose its selective control. Physical trauma, such as a concussion or traumatic brain injury (TBI), can physically disrupt the tight junctions between endothelial cells. This disruption increases the barrier’s permeability.
Inflammation is another cause of barrier disruption. Infections affecting the central nervous system, like meningitis, can trigger an immune response that weakens the BBB. Neurodegenerative diseases, including multiple sclerosis, Alzheimer’s, and Parkinson’s disease, are also associated with a progressive breakdown of the barrier, allowing inflammatory molecules to enter the brain.
A stroke, for instance, deprives brain tissue of oxygen, which can damage the endothelial cells and lead to increased permeability. Chronic conditions like high blood pressure and diabetes can also gradually weaken the barrier’s structure. When the BBB is compromised, substances that are normally blocked, such as toxins and various blood components, can enter the brain, leading to swelling and nerve damage.
Medical Strategies for Brain Drug Delivery
The blood-brain barrier’s protective function creates an obstacle for treating central nervous system disorders, blocking most drugs from entry. One strategy is to overcome this by designing small, lipophilic drugs that can passively diffuse across the barrier through careful chemical modification.
The “Trojan horse” method hijacks the brain’s natural transport systems. A therapeutic drug is attached to a molecule, like glucose, that has a natural transporter at the BBB. The transporter is tricked into carrying the attached drug into the brain, allowing large-molecule drugs to gain access.
Encapsulating drugs within nanoparticles is another promising avenue. These particles can be engineered to cross the barrier by interacting with receptors on the endothelial cells. A more direct method involves temporarily disrupting the barrier itself. Focused ultrasound, combined with microbubbles, can open the tight junctions in a specific region, allowing a drug to enter. This technique delivers therapeutics to precise locations while minimizing widespread disruption.