Breaking Down Barriers (Summer Science Series Pt. 2)

In microscopy, neuroscientists use photons (light particles) and electrons (charged particles) to zoom in on bits of brain tissue. And a select few scientists hunt for ways to image at higher and higher resolutions. It is impossible to image at a distance smaller than the wavelength at which your imaging particle oscillates, unless you get creative. In EyeWire’s past science posts, you’ll find the story of trying to overcome this imaging barrier but in this post we have another barrier to discuss: The blood-brain barrier, an INCREDIBLY selective blockade spanning almost the entire interface between blood vessels and the brain.

And what is a scientist to do with a barrier? Why, get through it of course! The blood-brain barrier prevents entry of foreign substances including infectious bacteria (which is awesome) and prescription drugs (not so awesome). The best methods for passing through the blood-brain barrier allow for more efficient drug administration without compromising the barrier’s ability to prevent infection.

Have scientists busted through the barrier yet? Well, sort of. A number of mechanisms have been designed to help drugs pass through the barrier, but none of them are perfect. The blood-brain barrier is a blockade of conjoined blood vessel cells, with sparse channels and transporters that allow the specific passage of molecules like glucose, oxygen, and hormones.

There is a balancing act to manipulating the barrier just enough to let in a drug, but not enough to make the brain vulnerable to bacterial threats. Currently, a drug called mannitol is one of the best methods for increasing blood-brain barrier permeability. Mannitol is a sugar alcohol used to manipulate the flow of water across membranes. It acts by absorbing water from the extravascular space, which shrivels the cells and thus, widens the spaces between them.

Unfortunately, it is difficult to target specific brain regions when administering mannitol, which puts the whole brain at risk of infection. Mannitol only works for about 5 minutes so it must be flawlessly administered through injection. It is difficult to predict how much of the drug will make it to the brain in time to open the blood brain barrier, and while too little drug is ineffective, too much drug could be seizure inducing.

Focused ultrasound is another heavily researched method for breaching the barrier. With the help of drug-carrying microbubbles, the barrier is weakened allowing the drug admission into the brain. In this case, focused ultrasound is used at an intensity that only disrupts the tissue. At higher intensities, the medical application of focused ultrasound is used for the ablation and destruction of tissue, making the application of this method precarious. Too many ultrasound sessions, and the damage done may outweigh the benefits. The tricky thing is, just enough of this treatment for one individual may be incredibly harmful for another.

Further methods include working within the barrier’s rules. The blood brain barrier is not impenetrable.

There are some passages that exist in the barrier and accept molecules with specific chemical characteristics, such as small, lipid soluble molecules that can pass through the barrier’s cell membranes. One example, L-dopa, is the blood-brain barrier friendly precursor for the neurotransmitter dopamine. L-dopa is endogenously converted into dopamine once it has passed through the barrier at which point it can help to treat Parkinson’s disease. Another molecule, insulin, can pass through the barrier via a transporter, and can thereafter regulate cognition and appetite. Both of these drugs follow the intense rules required for passing through the barrier. Though not all drugs can viably be engineered to pass, the most straightforward way to get through the barrier is not to disrupt it, but to play by it’s inherent permeability rules.

A notable property of the human brain is its large volume. Due to the volume, the distance between each capillary can be up to 50mm. Through any of the above drug treatment techniques, you may be administering toxic concentrations of your drug to the tissue surrounding a vessel in order to give an affective dose to deeper tissue. This universal obstacle is one of the greatest that researchers must overcome.

In summary, we are OK at getting through the blood brain barrier. It is a difficult task and the innovative nature of science and medicine will surely birth many methods and manipulations to come.

References for further reading:

http://www.ncbi.nlm.nih.gov/pubmed/25270115

http://www.nature.com/jcbfm/journal/v32/n11/full/jcbfm2012126a.html

http://www.ncbi.nlm.nih.gov/pubmed/22019122