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The Blood-Brain Barrier and the Future of Medicine

The blood-brain barrier, not quite a brick and mortar defense from the outside world, but strangely enough it is extremely effective. The blood-brain barrier (BBB) acts as a bouncer, it keeps the bad things out, while helping to regulate certain aspects of the brain. To circumvent the BBB thousands of people have stimulators placed deep in their brains in the hope of curing their ills. Many require tubes, catheters, and shunts penetrating deep into their brain ventricles to deliver medicine or to drain over pressurized cerebral fluids. These devices have a crude and bulky insertion that is simply plowed through healthy brain tissue, sparing little in its path. In other words, we need to do better.

Viruses, bacteria, fungi, parasitic tapeworms, or even cancer cells all have their own unique tricks for bypassing the BBB. Whether it is brute force penetration, deception, chemical stealth, or sheer overwhelming numbers, they will find a way in if the infection persists long enough. As the march towards industrially-scaled electronic miniaturization penetrates into various neuro-markets, it is inevitable that researchers will begin to see the BBB-busting skillsets of microbes applied to artificial devices for the brain.

To actually see this mysterious BBB, MRI images can be taken after the injection of paramagnetic gadolinium contrast agents into the bloodstream. These compounds generally stay within the cerebral vasculature and only leak out where the permeability of the BBB has altered from its natural state of health. Low concentrations of Gadolinium are typically prefered in these kinds of tests because of potential toxicity. But a study suggests there may be something better, by using superparamagnetic iron oxide particles encapsulated with inert hydrophilic polyethylene glycol (PEG), these researchers were able to obtain MRI images of the BBB as it dynamically responds to an assault.

The researchers call their carefully-engineered nanoparticles PEGylated SPIONs (because Superparamagnetic Iron Oxide Nanoparticles doesn’t sound cool enough , or maybe it’s just a mouthfull). These SPIONs proved particularly adept at enhancing T2-weighted images of the permeabilized BBB. Compared to the T1-weighted gadolinium scans. Don’t worry about the terminology if you don’t understand, just know that the T2-weighted scans can give greater detail in imaging various brain pathologies.

The researchers also were able to analyze the SPION label within the brain parenchyma itself. Again sorry abo5ut the terminology, the “parenchyma” is a catch-all term meaning the visceral or function parts of an organ. For the brain, that generally means the neurons and glial cells. We know, however, that there is much more to the brain than this. By some estimates, with over 100,000 miles of astrocytic endfeet-lined capillary tubing in its fractal coastline, the BBB and other membranous ventricular linings might be considered an organ itself.

The endothelial cells which line the BBB are similar to those found in any other organ yet are held to a slightly higher standard. The junctions they make are tighter, and subject to more points of control. There is also a sparse layer of pericytes above the endothelial cells, and above them are the tiling hands of astrocytes. Doctors today have a few crude tricks they can use to manipulate the BBB. They can administer mannose, for example, to osmotically pull fluid from the brain during hydrocephalus (also known as “water on the brain”). There are now signs that things may soon become more a little technically advanced than mannose and Ommaya shunts.

Non-invasive measurements of flow and pressure will be essential to understanding what is happening inside the brain when it has been altered by natural or by artificial means. One company is now offering instruments to record parameters through the skull within the micro-capillary bed. By measuring near IR light that has been modulated by ultrasound within the tissue through the acousto-optic effect they can directly gauge perfusion. These and other techniques may prove critical once we begin to heavily implant our brains with assistive technologies—and more critically perhaps, have medical issues with them.

We may even follow the lead of different diseases — like rabies, which not only hijacks the nervous system’s machinery, but speeds it up — and find some way to get around that pesky old blood-brain barrier. I bring up rabies simply because until now the way it did this was unknown to us, but in an interesting turn of events we have figured out how it works.  Whihc means we might just have a new way to access the brain.

“A tempting premise is to use this same machinery to introduce drugs or genes into the nervous system,” Dr.Eran Perlson said, co-author of the new paper.

You can find that paper in the sources section below. It will probably be quite some time until we can use anything like it in mainstream medicine, and until then we are unfortunately left in somewhat of the dark ages , with little more than brute force to get past the BBB.

Liu, D., Qian, C., An, Y., Chang, D., Ju, S., & Teng, G. (2014). Magnetic Resonance Imaging of Post-Ischemic Blood-Brain Barrier Damaging with PEGylated Iron Oxide Nanoparticles Nanoscale DOI: 10.1039/C4NR03942D

Gluska S, Zahavi EE, Chein M, Gradus T, Bauer A, Finke S, & Perlson E (2014). Rabies Virus Hijacks and Accelerates the p75NTR Retrograde Axonal Transport Machinery. PLoS pathogens, 10 (8) PMID: 25165859

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