[Several profs at Washington State, headed by Joe Harding in vet med] 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 learning and memory. 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 drug 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. .... In bench assays using living nerve cells 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.

¶ 5:04 PM