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Study Finds Endocannabinoid 2-AG Calms Seizures, Increases After Effects

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Diving into the science, potential benefits and pitfalls of everything cannabis offers often gives us further insight on our bodies and how they are built to interact with, or sometimes produce mirroring components, of cannabinoids entering the body. 

One study from Stanford University found that the release of the brain’s equivalent of THC, called 2-arachidonoylglycerol or 2-AG, can reduce seizure activity, though leads to post-seizure oxygen deprivation in the brain as well. 2-AG is itself an endocannabinoid, a short-lived substance that acts as one of the brain’s “internal versions” of the psychoactive cannabinoids in cannabis. Plant-derived cannabinoids and 2-AG share the need for a receptor, CB1, that can be found on the surface of neurons throughout the brain, according to the study.

Researchers noted that epileptic seizures trigger the “rapid synthesis and release” of 2-AG, which ultimately has the beneficial effect of dampening the intensity of a seizure. Because of the rapid breakdown of 2-AG following its release, however, the researchers observed that it causes the disorientation and amnesia that can follow an epileptic seizure.

The Stanford University scientists collaborated with colleagues at other institutions in the US, Canada and China.

“There have been lots of studies providing evidence for a connection between seizures and endocannabinoids,” said the study’s senior author and Professor of Neurosurgery Ivan Soltesz, PhD. “What sets our study apart is that we could watch endocannabinoid production and action unfold in, basically, real time.”

Most epileptic seizures begin at a single spot where nerve cells begin to fire repeatedly, in sync, with that hyperactivity spreading to other areas and causing seizure symptoms, like convulsions and loss of consciousness. According to the study, most epileptic seizures also originate in the hippocampus, which plays a role in short-term memory, learning and spatial orientation. Because it can quickly adopt new neuronal patterns, it is especially vulnerable to instances that can initiate seizures. 

Endocannabinoids in the brain are fragile and break down quickly, and until recently, there was not a way to measure those fast-changing levels in animal brains. That changed when Soltesz enacted a new endocannabinoid-visualization method invented by the study’s co-author, Yulong Li, PhD, a professor of neuroscience at Peking University in Beijing. The method bioengineers select neurons in mice so, when a cannabinoid binds to the modified endocannabinoid receptor, the neurons express a modified version of CB1, emitting a fluorescent glow.

The study monitored those split-second changes in levels of 2-AG in the hippocampus of mice during periods of normal activity, and in experiments, in which brief seizures were induced in the hippocampus.

The new research tool allowed scientists to monitor and localize those previously immeasurable, quick changes in fluorescence that correlate with endocannabinoid levels where the binding occurred.

The results proved that 2-AG alone is the endocannabinoid substance responsible for surges and rapid disappearance in the neuronal activity in mice. The research shows several-hundred times as much 2-AG was released when a mouse had a seizure compared to when it was running in place.

However, because 2-AG is almost immediately converted to arachidonic acid, it then acts to build inflammatory compounds called prostaglandins. The prostaglandins building up cause a constriction of tiny blood vessels in the brain, that can ultimately cut off oxygen supply to those brain areas, resulting in oxygen deprivation and cognitive deficits post-seizure.

While the research will likely need to continue before another substantial breakthrough, the discoveries from this study have the potential to help develop drugs that could curb the strength of seizures and reduce the after effects.

“A drug that blocks 2-AG’s conversion to arachidonic acid would kill two birds with one stone,” Soltesz said. “It would increase 2-AG’s concentration, diminishing seizure severity, and decrease arachidonic acid levels, cutting off the production of blood-vessel-constricting prostaglandins.”

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