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Posted: November 18, 2008

Hormone Shows Promise in Reversing Alzheimer's and Stroke

 

Researchers have identified a novel way of getting a potential treatment for Alzheimer’s disease and stroke into the brain where it can do its work. The process turns off a “gatekeeper” in the brain and allows drugs to enter the brain where they can do their job.

“We found a unique approach for delivering drugs to the brain,” says Dr. William A. Banks, professor of geriatrics and pharmacological and physiological science at Saint Louis University. “We’re turning off the guardian that’s keeping the drugs out of the brain.”

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The brain is protected by the blood-brain barrier (BBB), a gate-keeping system of cells that lets in nutrients and keeps out foreign substances. The blood-brain barrier passes no judgment on which foreign substances are trying to get into the brain to treat diseases and which are trying to do harm, so it blocks them without discrimination. This fact has caused a problem for researchers wanting to deliver drugs to the brain.

“The problem in treating a lot of diseases of the central nervous system -- such as Alzheimer’s disease, HIV and stroke -- is that we can’t get drugs past the blood-brain barrier and into the brain,” says Banks, who also is a staff physician at Veterans Affairs Medical Center in St. Louis.

“Our new research shows a way of getting a promising treatment for these types of devastating diseases to where they need to be to work.”

The therapy -- known as PACAP27 -- is a hormone produced by the body that is a general neuro-protectant. PACAP stands for pituitary adenylate cyclase-activating polypeptide. “It is a general protector of the brain against many types of insult and injury,” Banks says.

He compares a specific guarding mechanism in the BBB -- efflux pumps – to bouncers at exclusive nightclubs. While they welcome those on the approved guest list, they look for trouble-makers trying to crash the party, refuse to let them in and evict them if they do get in.

The scientists isolated the particular gatekeeper than evicts PACAP27. Then they designed an antisense, a specific molecule that turned off the impediment. “We went after the guard and essentially told him to go on break for a while so PACAP27 could get into the brain,” Banks says.

They used mouse models of Alzheimer’s disease and stroke to test what would happen if PACAP27 could get into the brain.

“We reversed the symptoms of the illnesses,” Banks says. “The mice that had a version of Alzheimer’s disease became smarter and in the stroke model, we reduced the amount of damage caused by the blockage of blood to the brain and improved brain recovery.”

Simply turning off the gatekeeper that kept PACAP27 out of the brain allowed enough of the hormone that already is in the body to get inside the brain, where it effectively treated strokes. However, the mice that had a version of Alzheimer’s disease needed both an extra dose of PACAP27 and the antisense that turned off the gatekeeper to improve learning.

“These findings are significant for three reasons. We have found a therapy that reverses symptoms of Alzheimer’s disease and stroke in a mouse model. We have isolated the particular roadblock that keeps the treatment from getting into the brain. And we have found a way to finesse that obstacle so the medicine can get into the brain to do its work,” Banks says. “This could have implications in treating many diseases of the central nervous system.”

The findings were published in the online issue of the Journal of Cerebral Blood Flow & Metabolism.

 

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