Marijuana-like brain chemicals could be key to treating fragile X syndrome

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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.”