Why The Blood Brain Barrier Is So Hard To Cross

The blood-brain barrier, a barricade of cells that prevent both harmful toxins and helpful pharmaceuticals from getting to the body’s center command, is one of the hardest parts of treating brain conditions, such as Alzheimer’s.

How tricky is it to get past this blockade?

So tricky that ninety-five per cent of all tested pharmacological agents for treating brain disorders fail, for the reason that they cannot cross the blood-brain barrier. Thus, the importance of finding a possible method for transporting drugs past the brain’s efficient protector is immense.

New research from the University of Copenhagen is shedding new on the brain’s complex barrier tissue. In an in vitro blood-brain barrier, researchers have recreated blood-brain barriers transport processes in a laboratory model, in order to develop new pharmaceuticals targeted to the brain.

Blood Brain Barrier Structure Bouncers

In the most recent study, the researchers have studied the disruptive bouncer proteins in the barrier tissue. These proteins protect the brain, but also stop the treatment of brain diseases.

“The blood-brain barrier is chemically tight because the cells contain transporter proteins which make sure that substances entering the cells are thrown straight back out into the bloodstream again. We have shown that the barrier which we have created in the laboratory contains the same bouncer proteins — and that they behave in the same way as in a ‘real’ brain. This is important, because the model can be used to test drive the difficult way into the brain. Complex phenomena — which we have so far only been able to study in live animals -can now be investigated in simple laboratory experiments using cultivated cells,” said postdoc Hans Christian Cederberg Helms.

The University of Copenhagen research team has demonstrated that the transporter proteins P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 1 are active in the artificially created blood brain barrier tissue.

“It is important to the treatment of brain diseases such as Alzheimer’s that we find a way of circumventing the brain’s effective defence. The university and industry must work together to overcome the fundamental challenges inherent in developing pharmaceuticals for the future,” says Lassina Badolo, of collaborating pharmaceutical company H. Lundbeck A/S, an expert on the absorption of medicines in the body.

These proteins pump pharmacological agents from the ‘brain side’ to the ‘blood side’ in the same way as in the human blood-brain barrier.

“We have shown that the models have the same bouncer proteins as the ones found in the intact barrier”, said associate Professor Birger Brodin. “We are now in the process of studying the proteins in the blood-brain barrier that accept pharmacological agents instead of throwing them out. If we can combine a beneficial substance which the brain needs with a so-called ‘absorber protein’, we will in the long term be able to smuggle pharmacological agents across the blood-brain barrier.”

Microbubbles, Ultrasound and Osmosis

One currently way of crossing the blood brain barrier is by using osmotic agents like mannitol. These agents are able suck the water out of the cells that form the barrier, causing the gaps between them to get bigger.

Unfortunately, this method opens large areas of the barrier, leaving the brain exposed to toxins.

A technique developed in 2012 by researchers at the Sunnybrook Research Institute and university of Toronto that uses an MRI machine to guide the use of microbubbles and focused ultrasound to help drugs enter the brain, could also open new treatment avenues for devastating conditions like Alzheimer’s and brain cancers.

The advantage of the microbubble technique is that it can be used on a tiny area of the blood brain barrier. The microbubbles, consisting of lipids and gas, are injected into the blood stream.

The bubbles expand and contract when focused ultrasound is applied. It is believed that the force of the movement in the bubbles causes the cells that form the blood-brain barrier to temporarily separate, which enables drugs to reach the brain.

Blood Brain Barrier Definition

Blood_vessels_brain_english
The blood–brain barrier refers to the highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system.

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 Ω⋅m.

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, do not have a blood–brain barrier.

The blood–brain barrier acts very effectively to protect the brain from many common bacterial infections. Thus, infections of the brain are very rare.

Infections of the brain that do occur are often very serious and difficult to treat. Antibodies are too large to cross the blood–brain barrier, and only certain antibiotics are able to pass.

For More Information:

Hans Christian Helms, Maria Hersom, Louise Borella Kuhlmann, Lasina Badolo, Carsten Uhd Nielsen, Birger Brodin.
An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1.
The AAPS Journal, 2014; DOI:10.1208/s12248-014-9628-1

O’Reilly, M. A., Waspe, A. C., Chopra, R., Hynynen, K.
MRI-guided Disruption of the Blood-brain Barrier using Transcranial Focused Ultrasound in a Rat Model.
J. Vis. Exp. (61), e3555, doi:10.3791/3555 (2012).

Choi, J. J., Wang, S., Tung, Y. -S., Morrison, B., Konofagou, E. E.
Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood-brain barrier opening in vivo.
Ultrasound Med. Biol.36, 58-67 (2010).

Photo credits, top to bottom: “Blood Brain Barriere” by Ben Brahim Mohammed – Own work. Licensed under Creative Commons Attribution 3.0 via Wikimedia Commons, darkday, “Blood vessels brain english” by Armin Kübelbeck – Licensed under Creative Commons Attribution 3.0 via Wikimedia Commons