A compound that was supposed to repair brain damage has become a promising medication for improving cognitive function in Alzheimer’s disease, Washington State University researchers reported in the Journal of Pharmacology and Experimental Therapeutics.

The scientists found that rats with Alzheimer’s-like cognitive impairment responded surprisingly well to the investigational drug.

They describe this medication as a “significant departure from current Alzheimer treatments”, which are aimed at slowing down disease progression or inhibiting an enzyme (cholinesterase), which is thought to break down a vital neurotransmitter involved in memory and learning development.

Joe Harding, a professor in the College of Veterinary Medicine, Washington State University, said current medication for Alzheimer’s have not been designed to restore brain function. In order to do this, connections between nerve cells need to be rebuilt.

Harding said:

“This is about recovering function. That’s what makes these things totally unique. They’re not designed necessarily to stop anything. They’re designed to fix what’s broken. As far as we can see, they work.”

Although research and development has been focusing strongly on seeking effective treatments for Alzheimer’s, there have only been three promising compounds that were approved over the last 13 years, out of 104 submissions, says PhRMA (Pharmaceutical Research and Manufacturers of America) – a ratio of 34 to 1.

In a communiqué, the PhRMA wrote:

“This 34 to one ratio of setbacks to successes underlines the difficulty of developing new medicines for Alzheimer’s.”

The authors stress that they are only at the initial stages of developing this potential Alzheimer’s medication. They will first have to convince the FDA (Food and Drug Administration) about its safety. It is only after the FDA is satisfied about an experimental drug’s safety that it will allow clinical trials to start. Clinical trials test drugs on human subjects. It is only with clinical trials that researchers can know whether a compound that works on laboratory animals has the same effect on humans.

Harding says that it may cost over $1 million just to find out whether the drug is safe. The team are seeking backers for the compound’s development.

Joe Harding, along with Jay Wright, a neurology professor at the College of Arts and Sciences, WSU, say they have been working on this compound for twenty years, when they began studying what the impact of angiotensin IV, a peptide, was on the hippocampus. The hippocampus is a part of the brain that is involved in short-term memory and spatial learning.

Scientists have known that angiotensins help regulate blood pressure. However, Wright and Harding learnt that early drug candidates based on angiotensins could reverse learning deficits seen in many dementia models.

These drug candidates were rapidly broken down by the body and could not penetrate the blood-brain barrier, making them useless as medications for restoring cognitive function. The blood-brain barrier is a barrier of cells that stops molecules, including most drugs from getting into the brain. The only way these medications could get into the brain would be by direct brain application.

Harding said:

“We said, ‘That’s useless. I mean, who wants to drill holes in people’s heads? It’s not going to work. It’s certainly not going to work for the big population.'”

In 2007, Harding designed Dihexa, a smaller version of the molecule. Dihexa has three promising features:

It can cross the blood-brain barrier.

It is stable.

It can move from the digestive system into the blood, meaning it can be taken orally as a pill.

The scientists treated a number of rats with scopolamine, a chemical that induces Alzheimer’s-like cognitive impairment, i.e. it interferes with a neurotransmitter that is vital for memory and learning. A rat that has been treated with scopolamine will never work out where a submerged platform in a water tank is, if it has to go only by cues outside the tank.

The researchers found that all of the rats managed to learn the location of the platform after they were given the WSU drug. The drug was administered directly into the brain, by injection into the body, and orally – in all three cases their cognitive skills improved dramatically. Harding said it was the “Same result, every time”.

They experimented on a small group of old rats and also observed improvements, albeit less dramatic ones. The old rats performed like the young rats after receiving the WSU drug.

The authors said their findings are statistically valid. However, they emphasized that further tests with more laboratory animals will be needed to confirm what they found.

The “gold standard” compound for creating connections between neurons is brain-derived neurotrophic factor (BDNF), a growth-promoting protein linked with learning and normal brain development. Alzheimer’s patients have lower-than-normal BDNF levels in their brains, according to autopsy reports.

Harding, Wright and team found that Dihexa is seven orders of magnitude more powerful than BDNF after using living nerve cells to monitor new neuronal connections, i.e. it would take 10 million times as much BDNF to achieve Dihexa’s new synapse formation volume.

Harding said “We quickly found out that this molecule was absolutely, insanely active.” The researchers believe that Dihexa or Dihexa-like molecules may be beneficial for treating brain traumas or other neurodegenerative diseases where neuronal connections have been lost.

Written by Christian Nordqvist