Prospective Antidementia Drug Improves Brain Function

A new antidementia drug candidate has been found to be highly active in creating new neuronal connections and improving the cognitive function of rats with Alzheimer’s-like mental impairment.

Researchers at Washington State University (WSU; Pullman, WA, USA) have developed a new compound, named Dihexa, designed to repair damage that has already occurred and thereby recover lost brain function. This is a significant departure from current treatments for diseases such as Alzheimer’s, treatments that only slow the process of cell death or inhibit the neurotransmitter cholinesterase. Also, the Pharmaceutical Research and Manufacturers of America (PhRMA) reported that only 3 of 104 possible treatments have been approved in the past 13 years, a 34 to 1 ratio of setbacks to successes.

Joe Harding, professor at the WSU College of Veterinary Medicine, Jay Wright, professor at the WSU College of Arts and Sciences, and other WSU colleagues, reported their findings on October 10, 2012, in the early online section of the Journal of Pharmacology and Experimental Therapeutics. Prof. Harding designed a smaller version of the peptide angiotensin IV. Unlike the original peptide and early candidate molecules based on it, the new analog, Dihexa, was found to be both stable and able to cross the blood-brain barrier. It can also move from the gut into the blood and so could be taken orally in pill form.

The WSU team tested Dihexa on several dozen rats treated with scopolamine. Typically, a rat treated with scopolamine will not learn the location of a submerged platform in a water tank, orienting with cues outside the tank. After receiving Dihexa, all rats learned the task whether receiving the drug orally, by injection, or directly into the brain. Similar results were observed where a smaller group of old rats performed like young rats after treatment; however, while these results were statistically valid, studies with larger test groups will be needed to check the finding.

The "gold standard” compound for creating neuronal connections is brain-derived neurotrophic factor (BDNF). In bench assays using living nerve cells to monitor new neuronal connections, Dihexa was seven orders of magnitude more powerful than BDNF, which itself has yet to be effectively developed for therapeutic use. "We quickly found out that this molecule was [very highly] active,” said Prof. Harding. These results further suggest that Dihexa or molecules like it may also have applications for other neurodegenerative diseases or brain traumas where neuronal connections are lost. Development of Dihexa for human use will begin after safety testing and US Food and Drug Administration approval is obtained for clinical trials.

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