Scientists at NIEHS reported that by pairing the antidepressant amitriptyline with drugs designed to treat central nervous system diseases, delivery of medication to the brain of rats is enhanced, due to inhibiting the blood-brain barrier. The blood-brain barrier serves as a natural, protective boundary, preventing most medicine from entering the brain. The research appeared online April 27 in the Journal of Cerebral Blood Flow and Metabolism.
Researchers cautioned that more studies are needed to determine whether people will benefit from the discovery. Even so, the new finding has the potential to revolutionize treatment for a whole host of brain-centered conditions, including epilepsy, stroke, human amyotrophic lateral sclerosis (ALS), depression, and others.
The results are so promising that a provisional patent application has been filed for methods of co-administration of amitriptyline with central nervous system drugs.
The pump that protects the brain
Lead researcher Ronald Cannon, Ph.D., was an NIEHS staff scientist in the Signal Transduction Laboratory (STL) at the time the work was performed. According to Cannon, the biggest obstacle to efficiently delivering drugs to the brain is a protein pump called P-glycoprotein. Located along the inner lining of brain blood vessels, P-glycoprotein directs toxins and pharmaceuticals back into the body’s circulation before they pass into the brain.
To get an idea of how P-glycoprotein works, Cannon compared the protein to a hotel doorman, standing in front of a revolving door at a lobby entrance. A person who is not authorized to enter would be turned away, ushered back around the revolving door and out into the street.
"For example, as good as vegetables are for us to eat, they have molecules that could be toxic if they slipped into the brain," Cannon said. "They don’t get in, because of P-glycoprotein, but this same protector also keeps out helpful therapeutics."
Amitriptyline turns off the pump
Cannon and his NIEHS colleagues initially found that amitriptyline significantly reduced P-glycoprotein’s pump activity in brain capillaries from wild-type rats. Later, they saw amitriptyline had the same effect in brain capillaries from genetically modified rats designed to mimic human ALS.
In both rat models, amitriptyline turned off P-glycoprotein within 10-15 minutes. When amitriptyline was removed, P-glycoprotein pump activity returned to full-strength.
NIEHS postbaccalaureate fellow David Banks is lead author on the paper and described amitriptyline’s action on P-glycoprotein as rapid and reversible, making the therapy so appealing.
"Most inventions developed at the bench don’t make it to the clinic, but I’m hopeful that our findings will translate into better treatment options for doctors and their patients," Banks said.
Cannon anticipates that administering amitriptyline along with a lower dose of an opioid could relieve pain and reduce the negative side effects, such as constipation and addiction, usually seen with higher doses of prescribed opioids.
“As our nation faces increases in Alzheimer’s disease, autism, and opioid abuse, we’re hopeful that this discovery will help address these serious health challenges,” said NIEHS and National Toxicology Program Director Linda Birnbaum, Ph.D.
Citation: Banks DB, Chan GNY, Evans RA, Miller DS, Cannon RE. 2017. Lysophosphatidic acid and amitriptyline signal through LPA1R to reduce p-glycoprotein transport at the blood-brain-barrier. J Cereb Blood Flow Metab; doi:10.1177/0271678X17705786 [Online 27 April 2017].