FOXNews.com: Marijuana-like brain chemicals could be key to treating fragile X syndrome

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Marijuana-like brain chemicals could be key to treating fragile X syndrome Sep 25th 2012, 15:43 In an international collaboration of research centers from America and Europe, scientists have revealed that increasing chemicals in the brain that act similarly to marijuana can help repair the debilitating symptoms associated with fragile X syndrome. The overall success of this study could lead to future treatments for the condition, which has been identified as the most common genetic basis for autism spectrum disorders.  The research was published in Nature Communications. The marijuana-like compound, called 2-AG, is a part of a class of chemicals called endocannabinoid transmitters.    These compounds are naturally made by the brain, and they act by combining to receptor proteins in the brain that marijuana chemicals also bind with. Fragile X syndrome is the result of a mutation of the FMR1 gene in the X chromosome passed on by the mother.   The condition occurs mostly in males because females typically have another X chromosome to compensate for the faulty X chromosome.  Symptoms of fragile X often include mental disability, walking and language delays and hyperactivity – as well as certain physical characteristics such as an elongated face and large ears. Finding this association between boosting 2-AG and the decline of fragile X symptoms was almost a shot in the dark, according to Daniele Piomelli of UC Irvine and lead study author Olivier Manzoni of INSERM, the French nation research agency . "This compound is so important in regulating neural transmission in the brain that it seemed possible that it might be involved in a disease that is so devastating on brain function," Piomelli told FoxNews.com. Piomelli explained most neurotransmitters in the brain work in a somewhat simple way.  Crucial for communication between cells, they are almost like one-way messaging systems.  For example, when an action needs to take place in the brain, 'Cell A,' – a neuron – will secrete a chemical (the neurotransmitter), which then travels to and binds with a designated 'Cell B.' The transmitter then activates the receiving cell or protein ('Cell B') so that it performs the function it needs to perform. About 99 percent of neurotransmitters behave in this way, Piomelli said.  However, during communication, sometimes there is a need for 'Cell A' to know what is happening in 'Cell B' – in case the receiving cell becomes too activated and releases too many chemicals.   In these cases, 'Cell B' will send a signal back to 'Cell A,' which will report on the conditions of 'Cell B.' "It's a retrograde signal – like a form of negative feedback," Piomelli said.  "When the cell is too active, it sends a signal saying, 'I'm too activated turn me off please.'  It's like an alarm, but it also turns off the production.  It's a circuit breaker in a sense." The retrograde chemical that Piomelli and his team focused on was 2-arachidonoyl glycerol, or 2-AG.  For individuals suffering from fragile X syndrome, their neurons are producing too much of the neurotransmitter glutamate.  In order for 2-AG to effectively slow down glutamate production, it must be produced at the right spot and at the right time.  However, fragile X brains have a more difficult time producing 2-AG. "It's extremely delicate machinery," Piomelli said.  "The cell must know exactly when there is too much of the transmitter.  If this machinery doesn't work very well, you don't produce enough glutamate.  If this machinery works too much, then too much glutamate is produced….This is an extremely delicate balance, and the brain has evolved ways to do that just right.  It's placed all the necessary proteins for all this reactions to occur perfectly.  What we discovered in fragile X mice is that this exquisite arrangement is all messed up." As a result of the machinery being off balance, too much glutamate is released into the system.  This causes the synapses in the brain to become hypersensitive and hyperactive – resulting in the physiological and behavioral problems that are associated with fragile X syndrome.   The imbalance in 2-AG and glutamate production is very small but leads to dramatic consequences. 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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