Neuron: Cannabis-like brain substances can calm seizures, but increase sequelae

But there is also a dark side

Scientists at Stanford University collaborated with colleagues from other institutions in the United States, Canada, and China to arrive at this discovery, which will be described in a study published in the journal Neuron on August 4

The researchers' findings can guide the development of drugs that can both suppress the intensity of epilepsy and reduce its sequelae

Electric storm in the brain

Approximately one in one hundred people suffers from epilepsy

Saltez is the James R.

In this study, Soltesz and his colleagues monitored the instantaneous changes in the level of 2-AG in the hippocampus of mice during normal activities (such as walking or running) and in experiments that induced transient epilepsy in the hippocampus

2-AG is an endocannabinoid, a member of the short-lived signaling substance family, and the internal version of the psychoactive chemicals in cannabis in the brain

"There have been many studies that have provided evidence for the link between seizures and endocannabinoids," Soltesz said

Suppress excitement

Endocannabinoids are believed to play a role in inhibiting hyperexcitability of the brain

When smoking marijuana fills the entire brain with relatively long-lasting THC, endocannabinoids are released at precise locations in the brain under precise circumstances, and their rapid decomposition will keep them active in a very short period of time, Soltesz said For decades, he has been studying the link between endocannabinoids and epilepsy

But because endocannabinoids are very fragile and decompose very fast, until recently there was a way to measure their rapidly changing levels in the animal brain

The most recent study began when Salters learned about a new method of visualization of endocannabinoids, which was invented by the co-author of the study and professor of neuroscience at Peking University, Dr.

Using this new tool, scientists can monitor and locate the sub-second changes in fluorescence associated with endocannabinoid levels, where this combination occurs

Align 2-AG

By blocking the key enzymes for the production and decomposition of different endocannabinoids, the researchers proved that 2-AG is the rapid increase and rapid disappearance of endocannabinoids to track the neuronal activity of mice

Researchers ruled out the possibility of endocannabinoids (anandamide), which many neurologists and pharmacologists believe is an active substance

Soltesz said: "This previously undetected activity-dependent surge in 2-AG levels down-regulates the excessive rhythmic excitement of excitatory neurons during seizures

But 2-AG is almost immediately converted to arachidonic acid, which is a component of an inflammatory compound called prostaglandin
.
The researchers found that the subsequent increase in arachidonic acid levels leads to the accumulation of a special prostaglandin, which leads to the contraction of tiny blood vessels in the brain.
Epilepsy leads to the production of prostaglandins, cutting off the oxygen supply to these brain regions
.

Sottez said that it is well known that hypoxia can cause cognitive impairment after epileptic seizures, such as disorientation and memory loss
.

"A drug that prevents the conversion of 2-AG to arachidonic acid will kill two birds with one stone," Soltesz said
.
It increases the concentration of 2-AG, reduces the severity of epilepsy, reduces the level of arachidonic acid, and cuts off the production of prostaglandins that constrict blood vessels

Soltesz is a member of Stanford Bio-X, the Wu Tsai Neuroscience Institute of Stanford University, and the Institute of Maternal and Child Health of Stanford University
.

Another research co-author at Stanford University is postdoctoral scholar Dr.
Barna Dudok
.

Other researchers from the University of Calgary and researchers from Vanderbilt University also participated in this work
.

The research was funded by the National Institutes of Health (K99NS117795, MH107435, 1S10OD017997-01A1, NS99457 and NS103558), Canadian Institutes of Health, Beijing Municipal Commission of Science and Technology, National Natural Science Foundation of China, and Peking University School of Life Sciences
.

The Department of Neurosurgery at Stanford University also supports this work
.

Journal Reference :

1. Jordan S.
   Farrell, Roberto Colangeli, Ao Dong, Antis G.
   George, Kwaku Addo-Osafo, Philip J.
   Kingsley, Maria Morena, Marshal D.
   Wolff, Barna Dudok, Kaikai He, Toni A.
   Patrick, Keith A.
   Sharkey, Sachin Patel, Lawrence J.
   Marnett, Matthew N.
   Hill, Yulong Li, G.
   Campbell Teskey, Ivan Soltesz.
   In vivo endocannabinoid dynamics at the timescale of physiological and pathological neural activity .
   Neuron , 2021; 109 (15): 2398 DOI: 10.
   1016/j.
   neuron.
   2021.
   05.
   026