Approaching the problem from both physiological and behavioral standpoints, Piomelli and his team of international researchers studied a group of genetically modified mice that exhibited essentially the same symptoms as fragile X humans.
They came to the conclusion that if 2-AG is not being produced at the right spot and time, enhancing its production may solve the problem. According to Piomelli, the brain is constantly making 2-AG and destroying it all the time. The brain produces an enzyme called monoacylglycerol lipase (MGL) that ultimately destroys 2-AG.
The scientists decided to use a compound that would inhibit the MGL enzyme, in order to give 2-AG a little boost in the brain.
“We asked, ‘If we boost a little bit of that 2-AG signal, will it be enough to correct the problems that occur in fragile X mice?’” Piomelli explained. “The answer was a resounding, ‘Yes.’” We corrected the physiology, but most importantly, we corrected their behavior. The animals behaved just like normal animals. They didn’t have the fears and movement problems of those with fragile X.”
Other recent drugs designed to treat fragile X also involve manipulating 2-AG production. In a recent study by Seaside Therapeutics in Cambridge, Mass., an experimental drug helped patients with fragile X develop better behavioral skills. According to Piomelli, that drug also involves 2-AG, but instead acts on the switch that turns on 2-AG signaling – a much different approach than that of Piomelli’s team.
With such encouraging outcomes from their study, Piomelli hopes to translate their results into therapy for humans. He cautioned that while it is not a treatment that will be available in the next couple years, the fact that the chemical is capable of being boosted with drugs is a major breakthrough in research of the condition.
“This is one of a few studies that has identified a specific problem in fragile X mice – which are an exact reproduction of fragile X in humans,” Piomelli said. “For us, it’s a great stimulus to do more in the next few years.”
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