Breaching the blood brain barrier

Dr. Weeks’ Comment:  The brain, that amazing organ which consumes twice as much sugar as other cells  and floats on a liquid cushion reducing its actual weight of 3 pounds to less than 1.2 pound  is also protected by the blood brain barrier. While that is a blessing to a health brain, if sick and requiring medication, it presents a problem.  A problem now being addressed!

 

Breaching the Blood-Brain Barrier: Finding May Permit Drug Delivery to the Brain for Alzheimer’s, Multiple Sclerosis and Brain Cancers

Sep. 14, 2011 — Cornell University researchers may have solved a 100-year puzzle: How to safely open and close the blood-brain barrier so that therapies to treat Alzheimer’s disease, multiple sclerosis and cancers of the central nervous system might effectively be delivered.

The researchers found that adenosine, a molecule produced by the body, can modulate the entry of large molecules into the brain. For the first time, the researchers discovered that when adenosine receptors are activated on cells that comprise the blood-brain barrier, a gateway into the blood-brain barrier can be established.
Although the study was done on mice, the researchers have also found adenosine receptors on these same cells in humans. They also discovered that an existing FDA-approved drug called Lexiscan, an adenosine-based drug used in heart imaging in very ill patients, can also briefly open the gateway across the blood-brain barrier.
The blood-brain barrier is composed of the specialized cells that make up the brain’s blood vessels. It selectively prevents substances from entering the blood and brain, only allowing such essential molecules as amino acids, oxygen, glucose and water through. The barrier is so restrictive that researchers couldn’t find a way to deliver drugs to the brain — until now.
“The biggest hurdle for every neurological disease is that we are unable to treat these diseases because we cannot deliver drugs into the brain,” said Margaret Bynoe, associate professor of immunology at Cornell’s College of Veterinary Medicine and senior author of a paper appearing Sept. 14 in the Journal of Neuroscience. Aaron Carman, a former postdoctoral associate in Bynoe’s lab, is the paper’s lead author. The study was funded by the National Institutes of Health.
“Big pharmaceutical companies have been trying for 100 years to find out how to traverse the blood-brain barrier and still keep patients alive,” said Bynoe, who with colleagues have patented the findings and have started a company, Adenios Inc., which will be involved in drug testing and preclinical trials.
Researchers have tried to deliver drugs to the brain by modifying them so they would bind to receptors and “piggyback” onto other molecules to get across the barrier, but so far, this modification process leads to lost drug efficacy, Bynoe said.
“Utilizing adenosine receptors seems to be a more generalized gateway across the barrier,” she added. “We are capitalizing on that mechanism to open and close the gateway when we want to.”
In the paper, the researchers describe successfully transporting such macromolecules as large dextrans and antibodies into the brain. “We wanted to see the extent to which we could get large molecules in and whether there was a restriction on size,” Bynoe said.
The researchers also successfully delivered an anti-beta amyloid antibody across the blood-brain barrier and observed it binding to beta-amyloid plaques that cause Alzheimer’s in a transgenic mouse model. Similar work has been initiated for treating multiple sclerosis, where researchers hope to tighten the barrier rather than open it, to prevent destructive immune cells from entering and causing disease.
Although there are many known antagonists (drugs or proteins that specifically block signaling) for adenosine receptors in mice, future work will try to identify such drugs for humans.
The researchers also plan to explore delivering brain cancer drugs and better understand the physiology behind how adenosine receptors modulate the blood-brain barrier.

Journal Reference:
Aaron J. Carman, Jeffrey H. Mills, Antje Krenz, Do-Geun Kim, Margaret S. Bynoe. Adenosine Receptor Signaling Modulates Permeability of the Blood–Brain Barrier. The Journal of Neuroscience, 2011; DOI: 10.1523/JNEUROSCI.3337-11.2011

 

AND 

 

Propping Open the Door to the Blood Brain

BarrierFeb. 1, 2013 — The treatment of central nervous system (CNS) diseases can be particularly challenging because many of the therapeutic agents such as recombinant proteins and gene medicines are not easily transported across the blood-brain barrier (BBB). Focused ultrasound can be used to “open the door” of the blood brain barrier.

However, finding a way to “prop the door open” to allow therapeutics to reach diseased tissue without damaging normal brain tissue is the focus of a new study by a team of researchers at the Institute of Biomedical Engineering at National Taiwan University presenting at the 57th Annual Meeting of the Biophysical Society (BPS), held Feb. 2-6, 2013, in Philadelphia, Pa.
The group is investigating the feasibility of using heparin, a common anticoagulant, to enhance the delivery of therapeutic macromolecules using ultrasound into the brain. Heparin could be employed to increase treatment efficacy in patients with different types of CNS diseases under the guidance of medical imaging system providing new hope in these challenging cases. Initial results show that heparin does have the potential to optimize therapeutic delivery with ultrasound, acting as a “doorstop,” allowing drugs to better permeate the BBB and enhancing treatment success.
“A higher acoustic pressure and longer sonication, and/or a higher dose of microbubbles may increase the delivery of drugs or tracers into the sonicated brain tissue,” explains Kuo-Wei Lu, a member of the research team, “but side-effects, such as microhemorrhage, can also increase dramatically. The results of this study indicate that heparin may offer a safer way can to enhance the delivery of therapeutics to patients with CNS diseases.”
With these encouraging results, the next step for the team is to develop a focused ultrasound system with Magnetic Resonance Imaging (MRI) guidance to establish suitable parameters needed for patient clinical trials. “Focused ultrasound sonication is a noninvasive technology capable of localized and transient BBB opening for the delivery of CNS therapeutics,” Lu states. “We hope by developing suitable parameters and using chemical enhancers like heparin, this can be a valuable tool in the treatment of patients with CNS diseases, opening the door to better patient outcomes.”

Story Source:
The above story is reprinted from materials provided by Biophysical Society, via Newswise.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Source of Article:  http://www.sciencedaily.com/releases/2013/02/130201095951.htm

 

Post Comment