Skip to main content

Drug Delivery to the Brain for Alzheimer's

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.

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 

Comments

Post a Comment

Popular posts from this blog

Neuronal Switch to Prevent Neurodegenerative Diseases

Scientists at Northwestern University report a surprising discovery that offers a possible new route for the treatment of neurodegenerative diseases. In a study of the transparent roundworm C. elegans, they found that a genetic switch in master neurons inhibits the proper functioning of protective cell stress responses, leading to the accumulation of misfolded and damaged proteins. Neurodegenerative diseases, ranging from Huntington's and Parkinson's to amyotrophic lateral sclerosis and Alzheimer's, are believed to stem from early events that lead to an accumulation of damaged proteins in cells. Yet all animals, including humans, have an ancient and very powerful mechanism for detecting and responding to such damage, known as the heat shock response. "Why are these diseases so widespread if our cells have ways to detect and prevent damaged proteins from accumulating?" said Richard I. Morimoto, who led the research together with postdoctoral colleague Veena Prah...
Post a Comment
Read more

J147 Reverses Memory Deficits And Slows Alzheimer's In Mice

Source:  Salk Institute A drug developed by scientists at the Salk Institute for Biological Studies, known as J147, reverses memory deficits and slows Alzheimer's disease in aged mice following short-term treatment. The findings, published May 14 in the journal Alzheimer's Research and Therapy, may pave the way to a new treatment for Alzheimer's disease in humans.  "J147 is an exciting new compound because it really has strong potential to be an Alzheimer's disease therapeutic by slowing disease progression and reversing memory deficits following short-term treatment," says lead study author Marguerite Prior, a research associate in Salk's Cellular Neurobiology Laboratory. Despite years of research, there are no disease-modifying drugs for Alzheimer's. Current FDA-approved medications, including Aricept, Razadyne and Exelon, offer only fleeting short-term benefits for Alzheimer's patients, but they do nothing to slow the steady, irr...
Post a Comment
Read more

New Way to Target Shape-Shifting Proteins

A molecule which can stop the formation of long protein strands, known as amyloid fibrils, that cause joint pain in kidney dialysis patients has been identified by researchers at the University of Leeds. The discovery could lead to new methods to identify drugs to prevent, treat or halt the progression of other conditions in which amyloid fibrils play a part, including Alzheimer's, Parkinson's and type II diabetes. The research, funded by the Biotechnology and Biological Sciences Research Council and the Wellcome Trust, is published August 28 in Nature Chemical Biology. The team -- from Leeds' Astbury Centre for Structural Molecular Biology and Faculty of Biological Sciences -- found that an antibiotic known as Rifamycin SV was able to prevent the protein β2microglobulin (β2m) from forming into fibrils. β2m is known to accumulate in renal dialysis patients and forms fibrils within the joints, causing extreme pain and arthritis. By using a specialised analytical technique ...
Post a Comment
Read more