Strategy developed to improve delivery of medicines to the brain

September 7, 2012

New research offers a possible strategy for treating central nervous system diseases, such as brain and spinal cord injury, brain cancer, epilepsy, and neurological complications of HIV. The experimental treatment method allows small therapeutic agents to safely cross the blood-brain barrier in laboratory rats by turning off P-glycoprotein, one of the main gatekeepers preventing medicinal drugs from reaching their intended targets in the brain.

The findings appeared online Sept. 4 in the , and is the result of a study from scientists at the National Institute of (NIEHS), part of the National Institutes of Health.

"Many fail because they cannot cross the blood-brain barrier sufficiently to provide a therapeutic dose to the brain," said David Miller, Ph.D., head of the Laboratory of Toxicology and Pharmacology at NIEHS, and leader of the team that performed the study. "We hope our new strategy will have a positive impact on people with in the future."

In a two-pronged approach, the research team first determined that treating rat brain capillaries with the multiple sclerosis drug marketed as Gilenya (fingolimod) stimulated a specific biochemical signaling pathway in the blood-brain barrier that rapidly and reversibly turned off P-glycoprotein. Team members then pretreated rats with fingolimod, and administered three other drugs that P-glycoprotein usually transports away from the brain. They observed a dramatic decline in P-glycoprotein transport activity, which led to a threefold to fivefold increase in brain uptake for each of the three drugs.

Ronald Cannon, Ph.D., is a staff scientist in the Miller lab and first author on the paper. He said one of the burning questions the team wants to tackle next is to understand how the signaling system turns off P-glycoprotein. He equates the mechanism to what happens when a person flips a light switch.

"If you physically turn off a light using the button on the wall, the light will go out because the electrical current to the light bulb has been interrupted," Cannon explained. "But what happens when the signaling pathway shuts down P-glycoprotein? Does it bring in another protein to bind to the pump, take away its energy source, modify the structure of the pump, or something else?"

Cannon said the paper's findings open a new way of thinking regarding targets for drug design, a thought that is emotionally gratifying for him and many other researchers whose scientific discoveries generally don't directly translate into helping people with illnesses.

"Although much more research needs to be done, delivering therapeutics to the central nervous system is one of the final frontiers of pharmacotherapy, Cannon added."

Explore further: Breaching the blood-brain barrier: Researchers may have solved 100-year-old puzzle

More information: Cannon RE, Peart JC, Hawkins BT, Campos CR, Miller DS. 2012. Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. Proc Natl Acad Sci U S A; doi:10.1073/pnas.1203534109 [Online 4 September 2012].

Related Stories

Breaching the blood-brain barrier: Researchers may have solved 100-year-old puzzle

September 13, 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 ...

South African daffodils may be a future cure for depression

June 22, 2012
Scientists at the University of Copenhagen have previously documented that substances from the South African plant species Crinum and Cyrtanthus – akin to snowdrops and daffodils – have an effect on the mechanisms ...

Recommended for you

Researchers describe mechanism that underlies age-associated bone loss

September 22, 2017
A major health problem in older people is age-associated osteoporosis—the thinning of bone and the loss of bone density that increases the risk of fractures. Often this is accompanied by an increase in fat cells in the ...

Researchers develop treatment to reduce rate of cleft palate relapse complication

September 22, 2017
Young people with cleft palate may one day face fewer painful surgeries and spend less time undergoing uncomfortable orthodontic treatments thanks to a new therapy developed by researchers from the UCLA School of Dentistry. ...

Exosomes are the missing link to insulin resistance in diabetes

September 21, 2017
Chronic tissue inflammation resulting from obesity is an underlying cause of insulin resistance and type 2 diabetes. But the mechanism by which this occurs has remained cloaked, until now.

Thousands of new microbial communities identified in human body

September 20, 2017
A new study of the human microbiome—the trillions of microbial organisms that live on and within our bodies—has analyzed thousands of new measurements of microbial communities from the gut, skin, mouth, and vaginal microbiome, ...

Study finds immune system is critical to regeneration

September 20, 2017
The answer to regenerative medicine's most compelling question—why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot—may lie with the body's innate immune system, ...

Immune cells produce wound healing factor, could lead to new IBD treatment

September 20, 2017
Specific immune cells have the ability to produce a healing factor that can promote wound repair in the intestine, a finding that could lead to new, potential therapeutic treatments for inflammatory bowel disease (IBD), according ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.