Prospective Alzheimer's drug builds new brain cell connections

Washington State University researchers have developed a new drug candidate that dramatically improves the cognitive function of rats with Alzheimer's-like mental impairment.

Their compound, which is intended to repair that has already occurred, is a significant departure from current Alzheimer's treatments, which either slow the process of cell death or inhibit cholinesterase, an enzyme believed to break down a key neurotransmitter involved in learning and memory development. Such drugs, says Joe Harding, a professor in WSU's College of Veterinary Medicine, are not designed to restore lost , which can be done by rebuilding connections between nerve cells.

"This is about recovering function," he says. "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."

Harding, College of Arts and Sciences Professor Jay Wright and other WSU colleagues report their findings in the online "Fast Forward" section of the Journal of Pharmacology and Experimental Therapeutics.

Their drug comes as the pharmacological industry is struggling to find an effective Alzheimer's treatment. Last month, the Pharmaceutical Research and Manufacturers of America, or PhRMA, reported that only three of 104 possible treatments have been approved in the past 13 years.

"This 34 to one ratio of setbacks to successes underlines the difficulty of developing for Alzheimer's," the trade group said in a news release. Development of the WSU drug is only starting. Harding and Wright must first satisfy the that it is safe. Only then would clinical trials begin to see if a drug that works in a rat will work in a human.

Safety testing alone could cost more than $1 million, says Harding, who is looking to fund the drug's development through his and Wright's company, M3 Biotechnology Inc., the WSU Research Foundation, and ultimately large pharmaceutical company partners.

Harding, a medicinal chemist, and Wright, a neuroscientist, have been working on their compound since 1992, when they started looking at the impact of the peptide angiotensin IV on the hippocampus, a brain region involved in spatial learning and short-term memory. Typically, angiotensins have been linked to blood pressure regulation, but Harding and Wright noticed that angiotensin IV, or early drug candidates based on it, were capable of reversing learning deficits seen in many models of dementia.

The practical utility of these early drug candidates, however, was severely limited because they were very quickly broken down by the body and couldn't get across the blood-brain barrier, a cellular barrier that prevents drugs and other molecules from entering the brain. The only way the drug could be delivered was by direct brain application.

Says Harding: "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.'"

Five years ago, Harding designed a smaller version of the molecule that he and Wright called Dihexa. Not only is it stable but it can cross the blood-brain barrier. An added bonus is it can move from the gut into the blood, so it can be taken in pill form.

The researchers tested the drug on several dozen rats treated with scopolamine, a chemical that interferes with a neurotransmitter critical to . Typically, a rat treated with scopolamine will never learn the location of a submerged platform in a water tank, orienting with cues outside the tank. After receiving the WSU drug, however, all of the rats did, whether they received the directly in the brain, orally, or through an injection.

"Same result, every time," says Harding.

Harding and Wright also reported similar but less dramatic results in a smaller group of old rats. In this study the old rats, which often have difficulty with the task, performed like young rats. While the results were statistically valid, additional studies with larger test groups will be necessary to fully confirm the finding. Currently, the "gold standard" compound for creating neuronal connections is brain-derived neurotrophic factor, or BDNF, a growth-promoting protein associated with normal brain development and learning. Autopsies of Alzheimer's patients have found lower levels of BDNF in the brain.

In bench assays using living to monitor new neuronal connections, Harding, Wright, and their colleagues found Dihexa to be seven orders of magnitude more powerful than BDNF, which has yet to be effectively developed for therapeutic use. In other words, it would take 10 million times as much BDNF to get as much new synapse formation as Dihexa.

"We quickly found out that this molecule was absolutely, insanely active," says Harding. These results further suggest that Dihexa or molecules like it may have applications in other neurodegenerative disease or brain traumas where are lost.

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alfie_null
5 / 5 (1) Oct 11, 2012
Can't help wondering how this drug might affect normal brains.
Sinister1811
not rated yet Oct 11, 2012
Well, if it works for Alzheimer's Disease, then it should work for other brain connectivity diseases as well.
The thing that confused me was this slight contradiction in the article:
He states that the drugs:
are not designed to restore lost brain function, which can be done by rebuilding connections between nerve cells.

And then he states:
They're designed to fix what's broken. As far as we can see, they work."

As far as I'm aware, these are practically the same thing. But, nevertheless, it's very promising research.
Howard_Vickridge
5 / 5 (2) Oct 11, 2012
@Sinister1811
No contradiction: the first statement you quote relates to current treatments; the second relates to this new molecule.

Sounds quite promising, here's hoping the funding is found to progress the research and subsequent human trials.
Sinister1811
not rated yet Oct 11, 2012
@Sinister1811
No contradiction: the first statement you quote relates to current treatments; the second relates to this new molecule.


Oops, my mistake. You are quite correct. I realized this after re-reading the article a second time. Just disregard the first comment. Furthermore, there's no "delete" button for posts, and the option to edit a post isn't permanent.
dogbert
3.7 / 5 (3) Oct 11, 2012
Sounds very promising. Hope they manage to continue with testing/development.

This drug might also work for other dementias such as multi-infarct, lewy body, etc.
PPihkala
5 / 5 (1) Oct 12, 2012
I just wish this would be on the market yesterday. While I'm writing this my 74-year-old mother is somewhere, missing for maybe 12 hours, because she left her apartment yesterday without her keys and cell phone. I can only hope we will find her in relatively good health.
Shakescene21
5 / 5 (1) Oct 14, 2012
The research seems promising, but I note that this research began in 1992. Twenty years later they are ready to test their improved chemical on rats for safety. Are we looking at another 20 years of testing? Altzheimers is worse than death -- why not let AD victims test it now?