Posts tagged blood–brain barrier

A new technique developed by Elisa Konofagou, professor of biomedical engineering and radiology at Columbia Engineering, has demonstrated for the first time that the size of molecules penetrating the blood-brain barrier (BBB) can be controlled using acoustic pressure—the pressure of an ultrasound beam—to let specific molecules through. The study was published in the July issue of the Journal of Cerebral Blood Flow & Metabolism.

“This is an important breakthrough in getting drugs delivered to specific parts of the brain precisely, non-invasively, and safely, and may help in the treatment of central nervous system diseases like Parkinson’s and Alzheimer’s,” says Konofagou, whose National Institutes of Health Research Project Grant (R01) funding was just renewed for another four years for an additional $2.22 million. The award is for research to determine the role of the microbubble in controlling both the efficacy and safety of drug safety through the BBB with a specific application for treating Parkinson’s disease.

Most small—and all large—molecule drugs do not currently penetrate the blood-brain barrier that sits between the vascular bed and the brain tissue. “As a result,” Konofagou explains, “all central nervous system diseases remain undertreated at best. For example, we know that Parkinson’s disease would benefit by delivery of therapeutic molecules to the neurons so as to impede their slow death. But because of the virtually impermeable barrier, these drugs can only reach the brain through direct injection and that requires anesthesia and drilling the skull while also increasing the risk of infection and limiting the number of sites of injection. And transcranial injections rarely work—only about one in ten is successful.”

Focused ultrasound in conjunction with microbubbles—gas-filled bubbles coated by protein or lipid shells—continues to be the only technique that can permeate the BBB safely and non-invasively. When microbubbles are hit by an ultrasound beam, they start oscillating and, depending on the magnitude of the pressure, continue oscillating or collapse. While researchers have found that focused ultrasound in combination with microbubble cavitation can be successfully used in the delivery of therapeutic drugs across the BBB, almost all earlier studies have been limited to one specific-sized agent that is commercially available and widely used clinically as ultrasound contrast agents. Konofagou and her team were convinced there was a way to induce a size-controllable BBB opening, enabling a more effective method to improve localized brain drug delivery.

Konofagou targeted the hippocampus, the memory center of the brain, and administered different-sized sugar molecules (Dextran). She found that higher acoustic pressures led to larger molecules accumulating into the hippocampus as confirmed by fluorescence imaging. This demonstrated that the pressure of the ultrasound beam can be adjusted depending on the size of the drug that needs to be delivered to the brain: all molecules of variant sizes were able to penetrate the opened barrier but at distinct pressures, i.e., small molecules at lower pressures and larger molecules at higher pressures.

“Through this study, we’ve been able to show, for the first time, that we can control the BBB opening size through the use of acoustic pressure,” says Konofagou. “We’ve also learned much more about the physical mechanisms associated with the trans-BBB delivery of different-sized agents, and understanding the BBB mechanisms will help us to develop agent size-specific focused ultrasound treatment protocols.”

Konofagou and her Ultrasound Elasticity Imaging Laboratory team plan to continue to work on the treatment of Alzheimer’s and Parkinson’s in a range of models, and hope to test their technique in clinical trials within the next five years.

“It is frightening to think that in the 21st century we still have no idea how to treat most brain diseases,” Konofagou adds. “But we’re really excited because we now have a tool that could potentially change the current dire predictions that come with a neurological disorder diagnosis.”

(Source: engineering.columbia.edu)

Research led by Queen Mary, University of London, has opened up the possibility that drug therapies may one day be able to restore the integrity of the blood-brain barrier, potentially slowing or even reversing the progression of diseases like multiple sclerosis (MS). The study, funded by the Wellcome Trust, is published in Proceedings of the National Academy of Sciences.

The blood-brain barrier (BBB) is a layer of cells, including endothelial cells, which line the blood vessels in the brain and spinal cord. These cells act as a barrier, stopping certain molecules, including immune cells and viruses, passing from the blood stream into the central nervous system (brain and spinal cord).

In a number of neurodegenerative brain diseases, including MS, the BBB is compromised, allowing inappropriate cells to pass into the brain with devastating consequences.

In this study the researchers identified a specific protein – known as Annexin A1 (ANXA1) – as being integral in maintaining the BBB in the brain. The authors initially found that mice bred to lack this protein showed a decrease in integrity of the BBB compared to controls.

Taking this finding, they then investigated the potential role of ANXA1 in conditions which involve progressive breakdown of the BBB, including MS and Parkinson’s disease, by examining post-mortem human brain tissue samples. ANXA1 was present in the cells of samples from individuals who did not have a neurological disease and also in samples from patients who had died with Parkinson’s disease. However, it was not detectable in the endothelial cells in samples from patients who had died with MS.

Crucially, the researchers found that treating in vitro brain endothelial cells with human recombinant ANXA1 restored the key cellular features needed to reinstate the integrity of the BBB. The same was seen with the ANXA1 knockout mice, where administering the protein reversed the permeability of the BBB within 24 hours.

Dr Egle Solito, from Barts and The London School of Medicine and Dentistry, part of Queen Mary, who co-ordinated the study said: “Our findings suggest this protein plays a key role in maintaining a functioning BBB and, more importantly, has the potential to rescue defects in the BBB. We now need to carry on our research to see how much this molecule may be exploited for therapeutic uses in conditions such as MS, or as a biomarker to help in early diagnosis.”

(Source: qmul.ac.uk)