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Entry from: 02.03.2018
Category: News, Press Releases

How to Overcome the Blood Brain Barrier

The blood brain barrier is a mighty obstacle. Some substances in the blood are toxic to the sensitive brain. The barrier protects the brain and prevents these substances from crossing into the brain environment. While this is of great benefit, the barrier also impedes the clinical use of potential drugs from reaching their destiny in the brain. Scientists have been long searching for ways to deliver drugs into the brain. Recently, Gerd Krause and his group from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin together with scientists from Charité, Berlin, Heidelberg (Germany), Vienna (Austria) and Rennes (France) discovered an option to open and close the blood brain barrier selectively by a biological tool. This tool consists of a protein isolated from bacteria and was modified to modulate the blood brain barrier in a targeted way. The study is published in the scientific journal 'Biomaterials'.

No other organ is as sensitive as the brain. To protect the sensitive nerve cells from poisonous substances and pathogens, land-dwelling vertebrates including humans developed their blood brain barrier as boundary of protection. The barrier consists of endothelial cells, which line the blood vessels inside the brain. A network of proteins forms tight junctions that tightly assemble the cells and seal the interstitial spaces.

Only very small or fat-soluble (lipophilic) molecules such as alcohol are able to penetrate the blood brain barrier. Dr. Gerd Krause who works at the FMP explains, "Many drugs could be useful for the treatment of brain tumors and neurodegenerative diseases such as Alzheimer's Disease if they could penetrate the blood brain barrier." With funding from the Deutsche Forschungsgemeinschaft (DFG; German Research Association) Dr. Krause and his team searched for a method to open the blood brain barrier for a brief time before allowing it to close again.


A modified bacterial protein fragment served as gate opener.


The major tight junction protein of the blood brain barrier goes by the name of Cldn5. The protein belongs to the claudin family of proteins. Dr. Krause elaborates, "Therefore, we surmised that an enterotoxin synthesized by Clostridium perfringens bacteria would be a promising door opener candidate."  Usually, this CPE protein (C. perfringens enterotoxin) binds to Cldn3 and Cldn4 but not to Cldn5.

To strip CPE of its toxic nature, the scientists used only the section of the protein, which contains the binding domain for claudin proteins. In the next step, they worked on modifying the protein in such a way that it attaches to Cldn5 and in this way opens the blood brain barrier.

In a computer simulation, Dr. Jonas Protze at the FMP first examined the three-dimensional crystal structure of the CPE protein while it interacts with Cldn5. "This told us which amino acids were responsible for the fact that the two proteins did not fit together like lock and key", explained Dr. Protze. Still in the computer simulation, the scientists deliberately exchanged particular amino acids in the CPE protein until they achieved an improved fit for the Cldn5 attachment site.


The protective barrier closed tightly again as desired.


Dr. Anna Piontek at the FMP grew specific E. coli strains according to the specifications of Dr. Protze. These E. coli bacteria synthesized the modified CPE.
Dr. Piontek describes: "In the next step, we performed experiments with brain endothelial cells from mice, rats and pigs. The scientists found that the presence of modified CPE reduces the electrical resistance of the epithelial cells. The drop in resistance depends on the concentration of modified CPE. Lower resistance resulted also in higher permeability of the protective barrier for drug-like substances.

"In addition, our experiments showed that the presence of the modified CPE protein does not destroy the tight junctions." In a joint effort with the teams around Dr. Winfried Neuhaus in Vienna and Dr. Jörg Piontek at the Charité Berlin proved that the increased permeability of the endothelial layer is reversible and can be reversed within one hour. This was an important finding for the scientists who never lost sight of the important function of the blood brain barrier in living organisms. As their next step, the scientists plan to test the blood brain barrier modulation in laboratory mice.


Winfried Neuhaus, Anna Piontek, Jonas Protze, Miriam Eichner, Anne Mahringer, Eva-Anne Subileau, In-Fah M. Lee, Jörg D. Schulzke, Gerd Krause, Jörg Piontek: Reversible opening of the blood-brain barrier by claudin-5-binding variants of Clostridium perfringens enterotoxin’s claudin-binding domain
Biomaterials 2018 161:129-143
doi.org/10.1016/j.biomaterials.2018.01.028


Contact:

Dr. Gerd Krause
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
gkrause(at)fmp-berlin.de
Tel.: 0049 30 94793-190
www.leibniz-fmp.de/gkrause


Public Relations
Silke Oßwald
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Tel.: +49-30-94793-104
E-Mail: osswald(at)fmp-berlin.de


The Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) is part of the Forschungsverbund Berlin e.V. (FVB), who legally represents eight non-university research institutes - members of the Leibniz Association - in Berlin. The institutions pursue common interests within the framework of a single legal entity while maintaining their scientific autonomy. More than 1,900 employees work within the research association. The eight institutes were founded in 1992 and emerged from former institutes of the GDR Academy of Sciences.

Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)
info(at)fmp-berlin.de

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