A
study reveals a previously unknown way in which cannabidiol (CBD), a
substance found in cannabis, reduces seizures in many
treatment-resistant forms of pediatric epilepsy.
The new study found that CBD blocked signals carried by a molecule
called lysophosphatidylinositol (LPI). Found in brain cells called
neurons, LPI is thought to amplify nerve signals as part of normal
function, but can be hijacked by disease to promote seizures.
Published in Neuron, the work confirmed a previous finding that
CBD blocks the ability of LPI to amplify nerve signals in a brain
region called the hippocampus. The current findings argue for the first
time that LPI also weakens signals that counter seizures, further
explaining the value of CBD treatment.
“Our results deepen the field’s understanding of a central
seizure-inducing mechanism, with many implications for the pursuit of
new treatment approaches,” said the corresponding author.
“The study also clarified, not just how CBD counters seizures, but more
broadly how circuits are balanced in the brain,” added the author.
“Related imbalances are present in autism and schizophrenia, so the
paper may have a broader impact.”
The study results build on how each neuron “fires” to send an electrical
pulse down an extension of itself until it reaches a synapse, the gap
that connects it to the next cell in a neuronal pathway. When it reaches
the cell’s end before the synapse, the pulse triggers the release of
compounds called neurotransmitters that float across the gap to affect
the next cell in line. Upon crossing, such signals either encourage the
cell to fire (excitation), or apply the brakes on firing (inhibition).
Balance between the two are essential to brain function; too much
excitation promotes seizures.
The new study looked at several rodent models to explore mechanisms
behind seizures, often by measuring information-carrying electrical
current flows with fine-tipped electrodes. Other experiments looked at
the effect of LPI by genetically removing its main signaling partner, or
by measuring the release of LPI following seizures.
The tests confirmed past findings that LPI influences nerve signals by
binding to a protein called G-coupled receptor 55 (GPR55), on neuron
cell surfaces. This LPI-GPR55 presynaptic interaction was found to cause
the release of calcium ions within the cell, which encouraged cells to
release glutamate, the main excitatory neurotransmitter. Further, when
LPI activated GPR55 on the other side of the synapse, it weakened
inhibition, by decreasing the supply and proper arrangement of proteins
necessary for inhibition. Collectively, this creates a “dangerous”
two-pronged mechanism to increase excitability, say the authors.
The research team found that either genetically engineering mice to lack
GPR55, or treating mice with plant-derived CBD prior to
seizure-inducing stimuli, blocked LPI-mediated effects on both
excitatory and inhibitory synaptic transmission. While prior studies had
implicated GPR55 as a seizure-reducing target of CBD, the current work
provided a more detailed, proposed mechanism of action.
The authors propose that CBD blocks a “positive feedback loop” in which
seizures increase LPI-GPR55 signaling, which likely encourages more
seizures, which in turn increases levels of both LPI and GPR55. The
proposed vicious cycle provides one process that could explain repeated
epileptic seizures, although future studies are needed to confirm this.
Further, the current study examined the plant-based cannabinoid CBD, but
the authors note that LPI is part of signaling network that includes
“endocannabinoids” like 2-Arachidonoylglycerol (2-AG) that
occur naturally in human tissues. LPI and 2-AG target receptors also
regulated by CBD, but have different actions at the synapse. While LPI
amplifies incoming electrical signals, endocannabinoids like 2-AG
respond to increases in brain activity by dialing down the release of
neurotransmitters from nerve cells. Interestingly, LPI and 2-AG can be
converted into each other through actions of enzymes.
“Theoretically, the brain could control activity by toggling between
pro-excitatory LPI and the restorative actions of 2-AG,” said the first
study author. “Drug designers could inhibit the enzymes that underpin
LPI production or promote its conversion to 2-AG, as an additional
approach to control seizures. LPI could also serve as a biomarker of
seizures or predictor of clinical responsiveness to CBD, providing an
area of future research.”
https://www.cell.com/neuron/fulltext/S0896-6273(23)00066-1
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fcannabidiol-modulates&filter=22