Marijuana-like brain substance calms seizures but increases
aftereffects, study finds

Date:
August 4, 2021
Source:
Stanford Medicine
Summary:
Release of the brain's equivalent of THC, marijuana's active
component, reduces seizure activity but leads to post-seizure
oxygen deprivation in the brain, scientists have shown.



FULL STORY ========================================================================== Epileptic seizures trigger the rapid synthesis and release of a substance mimicked by marijuana's most psychoactive component, Stanford University
School of Medicine investigators have learned. This substance is called 2- arachidonoylglycerol, or 2-AG, and has the beneficial effect of damping
down seizure intensity.


==========================================================================
But there's a dark side. The similarly rapid breakdown of 2-AG after
its release, the researchers found, trips off a cascade of biochemical reactions culminating in blood-vessel constriction in the brain and, in
turn, the disorientation and amnesia that typically follow an epileptic seizure.

The Stanford scientists' findings, reached in collaboration with
colleagues at other institutions in the United States, Canada and China,
are described in a study to be published Aug. 4 in Neuron. Ivan Soltesz,
PhD, professor of neurosurgery, shares senior authorship with G. Campbell Teskey, PhD, professor of cell biology and anatomy at the University of
Calgary in Alberta, Canada.

The study's lead author is Jordan Farrell, PhD, a postdoctoral scholar
in Soltesz's group.

The researchers' discoveries could guide the development of drugs that
both curb seizures' strength and reduce their aftereffects.

Electrical storm in the brain About one in every hundred people has
epilepsy. Epileptic seizures can be described as an electrical storm
in the brain. These storms typically begin at a single spot where nerve
cells begin repeatedly firing together in synchrony.

The hyperactivity often spreads from that one spot to other areas
throughout the brain, causing symptoms such as loss of consciousness and convulsions. It's typical for the person experiencing a seizure to need
tens of minutes before becoming clearheaded again.



==========================================================================
The majority of epileptic seizures originate in the hippocampus, a
brain structure buried in the temporal lobe, said Soltesz, the James
R. Doty Professor of Neurosurgery and Neurosciences. The hippocampus
plays an outsized role in short-term memory, learning and spatial
orientation. Its ability to quickly adopt new neuronal firing patterns
renders it especially vulnerable to glitches that initiate seizures. (Most epileptic seizures in adults begin in or near the hippocampus, Soltesz
noted.) In the study, Soltesz and his associates monitored split-second changes in levels of 2-AG in the hippocampus of mice during periods of
normal activity, like walking or running, and in experiments in which
brief seizures were induced in the hippocampus.

2-AG is an endocannabinoid, a member of a family of short-lived
signaling substances that are the brain's internal versions of the
psychoactive chemicals in marijuana. 2-AG and these plant-derived
psychoactive chemicals share an affinity for a receptor, known as CB1,
that's extremely abundant on the surface of neurons throughout the brain.

"There have been lots of studies providing evidence for a connection
between seizures and endocannabinoids," Soltesz said. "What sets our
study apart is that we could watch endocannabinoid production and action
unfold in, basically, real time." A brake on excitement Endocannabinoids
are understood to play a role in inhibiting excessive excitement in the
brain. When excitatory neurons, secreting chemical "go" signals, exceed
a threshold, they induce the production and release of endocannabinoids,
whose binding to CB1 on an excitatory neuron acts as a brake, ordering
that neuron to chill out a little.



========================================================================== While smoking marijuana floods the entire brain with relatively
long-lasting THC, endocannabinoids are released in precise spots in the
brain under precise circumstances, and their rapid breakdown leaves them
in place and active for extremely short periods of time, said Soltesz,
who has been studying the connection between endocannabinoids and epilepsy
for decades.

But because endocannabinoids are so fragile and break down so quickly,
until recently there was no way to measure their fast-changing levels
in animals' brains. "Existing biochemical methods were far too slow,"
he said.

The most recent study had its start when Soltesz learned of a new endocannabinoid-visualization method invented by study co-author Yulong
Li, PhD, a professor of neuroscience at Peking University in Beijing. The method involves the bioengineering of select neurons in mice so that these neurons express a modified version of CB1 that emits a fluorescent glow whenever a cannabinoid binds to the modified endocannabinoid receptor. The fluorescence can be detected by photosensitive instruments.

Using this new tool, the scientists could monitor and localize sub-second changes in fluorescence that correlate with endocannabinoid levels where
that binding was occurring.

Zeroing in on 2-AG By blocking enzymes critical to the production and
breakdown of different endocannabinoids, the researchers proved that
2-AG alone is the endocannabinoid substance whose surges and rapid disappearance track neuronal activity in the mice. Several hundred times
as much 2-AG was released when a mouse was having a seizure compared
with when it was merely running in place.

The researchers were able to rule out the involvement of an alternative endocannabinoid, anandamide, that many neuroscientists and pharmacologists
had assumed was the active substance. Anandamide's name is derived
from the Sanskrit word for "bliss." "This previously undetected activity-dependent surge in levels of 2-AG downregulates excitatory
neurons' excessive rhythmic firing during a seizure," Soltesz said.

But 2-AG is almost immediately converted to arachidonic acid, a building
block for inflammatory compounds called prostaglandins. The researchers
showed that the ensuing increase in arachidonic acid levels resulted
in the buildup of a particular variety of prostaglandin that causes constriction of tiny blood vessels in the brain where the seizure has
induced thatprostaglandin's production, cutting off oxygen supply to
those brain areas.

Oxygen deprivation is known to produce the cognitive deficits - - disorientation, memory loss -- that occur after a seizure, Soltesz said.

"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." Soltesz is a member of Stanford Bio-X, the Wu Tsai Neurosciences Institute at Stanford, and the Stanford Maternal and Child
Health Research Institute.

Another Stanford co-author of the study is postdoctoral scholar Barna
Dudok, PhD.

Other researchers at the University of Calgary, as well as researchers
at Vanderbilt University, contributed to the work.

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

Stanford's Department of Neurosurgery also supported the work.

========================================================================== Story Source: Materials provided by Stanford_Medicine. Original written
by Bruce Goldman.

Note: Content may be edited for style and length.


========================================================================== 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210804123457.htm

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