The blood–brain barrier (BBB) is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid (BECF) in thecentral nervous system (CNS). It keeps toxins in the bloodstream away from the brain. The blood–brain barrier is formed by capillary endothelial cells, which are connected by tight junctions with an extremely high electrical resistivity of at least 0.1 Ωm. The blood–brain barrier allows the passage of water, some gases, and lipid soluble molecules by passive diffusion, as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function. On the other hand, the blood–brain barrier may prevent the entry of lipophilic, potential neurotoxins by way of an active transport mechanism mediated by P-glycoprotein. Astrocytes are necessary to create the blood–brain barrier. A small number of regions in the brain, including the circumventricular organs (CVOs), do not have a blood–brain barrier.
The blood–brain barrier occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion of microscopic objects (e.g., bacteria) and large or hydrophilic molecules into the cerebrospinal fluid (CSF), while allowing the diffusion of small hydrophobic molecules (O2, CO2, hormones). Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins. This barrier also includes a thick basement membrane and astrocytic endfeet.
Kullervo Hynynen is preparing to cross neuroscience’s final frontier. In July he will work with a team of doctors in the first attempt to open the blood-brain barrier in humans – the protective layer around blood vessels that shields our most precious organ against threats from the outside world.
If successful, the method would be a huge step in the treatment of pernicious brain diseases such as cancer, Parkinson’s and Alzheimer’s, by allowing drugs to pass into the brain.
The downside of this is that the BBB also completely blocks the vast majority of drugs. Exceptions include some classes of fat and lipid-soluble chemicals, but these aren’t much help as such drugs penetrate every cell in the body – resulting in major side effects.
“Opening the barrier is really of huge importance. It is probably the major limitation for innovative drug development for neurosciences,” says Bart De Strooper, co-director of the Leuven Institute for Neuroscience and Disease in Belgium.
Hynynen, a medical physicist at Sunnybrook Research Institute in Toronto, Canada, thinks the answer lies in gas-filled microbubbles. These were discovered accidentally in the 1960s when radiologists noticed that tiny bubbles in blood made ultrasound images clearer. More recently, they have been investigated as a way to help treat hard-to-reach cancers.
Hynynen’s trial will involve 10 people with a cancerous brain tumour. First, the volunteers will be given a chemotherapy drug that does not usually cross the BBB. They will then receive an injection of microbubbles, which will spread throughout the body, including into the blood vessels that serve the brain.
Next is a treatment called high-intensity focused ultrasound. The volunteers will wear a cap that contains an array of transducers that direct ultrasound waves into their brain. Just as the sun’s rays can be focused by a magnifying glass, ultrasound waves can be concentrated inside the body to get the microbubbles to vibrate.