Cornell researchers have discovered a way to penetrate the blood brain barrier (BBB) that may soon permit delivery of drugs directly into the brain to treat disorders such as Alzheimer’s disease and chemotherapy-resistant cancers.

The BBB is a layer of endothelial cells that selectively allow entry of molecules needed for brain function, such as amino acids, oxygen, glucose and water, while keeping others out.

Cornell researchers report that an FDA-approved drug called Lexiscan activates adenosine receptors that are expressed on these BBB cells.

“We can open the BBB for a brief window of time, long enough to deliver therapies to the brain, but not too long so as to harm the brain. We hope in the future, this will be used to treat many types of neurological disorders,” said Margaret Bynoe, associate professor in the Department of Microbiology and Immunology in Cornell’s College of Veterinary Medicine. Bynoe is senior author of the study, which appears in The Journal of Clinical Investigation.

Bynoe’s team was able to deliver chemotherapy drugs into the brains of mice, as well as large molecules, like an antibody that binds to Alzheimer’s disease plaques, according to the paper.

The lab also engineered a BBB model using human primary brain endothelial cells, where they observed that Lexiscan opened the engineered BBB in a manner similar to its actions in mice.

Bynoe and her team discovered that a protein called P-glycoprotein is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain.

Lexiscan acts on one of the adenosine receptors expressed on BBB endothelial cells specifically activating them.

They showed that Lexiscan down-regulates P-glycoprotein expression and function on the BBB endothelial cells. It acts like a switch that can be turned on and off in a time dependent manner, which provides a measure of safety for the patient.

“We demonstrated that down-modulation of P-glycoprotein function coincides exquisitely with chemotherapeutic drug accumulation” in the brains of mice and across an engineered BBB using human endothelial cells, Bynoe said. “The amount of chemotherapeutic drugs that accumulated in the brain was significant.”

In addition to P-glycoprotein’s role in inhibiting foreign substances from penetrating the BBB, the protein is also expressed by many different types of cancers and makes these cancers resistant to chemotherapy.

“This finding has significant implications beyond modulation of the BBB,” Bynoe said. “It suggests that in the future, we may be able to modulate adenosine receptors to regulate P-glycoprotein in the treatment of cancer cells resistant to chemotherapy.”

Because Lexiscan is an FDA-approved drug,”the potential for a breakthrough in drug delivery systems for diseases such as Alzheimer’s disease, Parkinson’s disease, autism, brain tumors and chemotherapy-resistant cancers is not far off,” Bynoe said.

Article: Journal of Clinical Investigation