Findings Suggest Specific Targets for Future
Drugs
NEW
YORK, Feb. 13, 2023 /PRNewswire/ -- A study
reveals a previously unknown way in which cannabidiol (CBD), a
substance found in cannabis, reduces seizures in
treatment-resistant forms of pediatric epilepsy.
Led by researchers at NYU Grossman School of Medicine, 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 online February 13 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 corresponding author
Richard W. Tsien, chair of the
Department of Physiology and Neuroscience at NYU Langone
Health.
"The study also clarified, not just how CBD counters seizures,
but more broadly how circuits are balanced in the brain," added
Tsien. "Related imbalances are present in autism and schizophrenia,
so the paper may have a broader impact."
Disease-Causing Loop
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 the necessary
proteins. 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 that are 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 first study author Evan
Rosenberg, PhD, a post-doctoral scholar in the Tsein's lab.
"Drug designers could inhibit the enzymes that enable 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."
Along with Tsien and Rosenberg, study authors in the Department
of Neuroscience & Physiology and Neuroscience Institute at NYU
Langone Health were Simon
Chamberland, Erica Nebet, Xiaohan
Wang, Sam McKenzie, Alejandro
Salah, Nicolas Chenouard, Simon Sun,
and György Buzsáki. Also NYU Langone authors were Orrin Devinsky in the Department of Neurology,
Rebecca Rose in the Department of
Advanced Research Technologies, and Drew
Jones in the Department of Biochemistry and Molecular
Pharmacology. Also study authors were Michael Bazelot, Shanice Bailey, Pabitra
Hriday Patra, and Benjamin
Whalley at the School of Chemistry, Food and Nutritional
Sciences, and Pharmacy, University of Reading, Hopkins Life Science Building,
Whiteknights, Reading, United
Kingdom; Swati Jain and
Helen Scharfman in the Departments
of Child and Adolescent Psychiatry, Neuroscience & Physiology,
and Psychiatry at NYU, and the Center
for Dementia Research at the Nathan Kline Institute for Psychiatric
Research; Stuart Greenhill,
Max Wilson, Nicole Marley, and Gavin
Woodhall of the Aston Neuroscience Institute, School of Life
and Health Sciences at Aston University in Birmingham, United Kingdom.
This work was supported by funding from the Ruth L. Kirschstein
National Research Service Awards (NRSA) for Individual Pre-doctoral
MD/PhDs (F30 NS100293), the NYU MSTP Training Grant (T32GM007308),
as well as by National Institutes of Health grant (NIMH)
5R37MH071739), NIDA grant DA040484-01, the Simons Foundation, the
Vulnerable Brain Project, FACES (Finding a Cure for Epilepsy &
Seizures), the Charles H. Revson Senior Fellowship in Biomedical
Science, the Andrew Ellis and Emily Segal
Investigator Grant from the Brain and Behavior Research
Foundation, a postdoctoral fellowship from the Fonds de Recherche
du Québec - Santé (FRQS), and a K99/R00 Pathway to Independence
Award from NIMH (1K99MH126157-01). The services of the NYU
Metabolomics Core and Experimental Pathology Research Laboratory
Core were supported by Perlmutter Cancer Center Support Grant
P30CA016087.
Contact:
Gregory Williams
gregory.williams@nyulangone.org
View original content to download
multimedia:https://www.prnewswire.com/news-releases/study-reveals-how-cbd-counters-epileptic-seizures-301745673.html
SOURCE NYU Grossman School of Medicine and NYU Langone
Health
