This microscope image of the brain region called the hippocampus shows the protein targeted by cannabis-derived CBD, GPR55 (red), and brain cells (blue) that send their extensions out to form the layers seen in the image. The interconnected nature of the hippocampus makes it a significant site of for the initiation and spread of seizures. Credit: Tsien et al, Courtesy of Cell Press
Study findings recommend specific targets for future drugs.
A previously unknown method in which cannabidiol (CBD), a compound found in marijuana, minimizes seizures in lots of treatment-resistant forms of pediatric epilepsy has been revealed by a brand-new scientific research study.
Led by scientists at NYU Grossman School of Medicine, the research study found that CBD blocked signals carried by a particle called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to magnify nerve signals as part of typical function, however can be pirated by disease to promote seizures.
Published online on February 13 in the journal Neuron, the work verified a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain area called the hippocampus. The existing findings argue for the first time that LPI also damages signals that counter seizures, further discussing the value of CBD treatment..
Credit: Tsien et al, Courtesy of Cell Press
The research study results develop on how each nerve cell “fires” to send out an electrical pulse down an extension of itself till it reaches a synapse, the gap that links it to the next cell in a neuronal pathway. When it reaches the cells end prior to the synapse, the pulse sets off the release of compounds called neurotransmitters that drift throughout the space to impact the next cell in line. 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. While LPI amplifies inbound electrical signals, endocannabinoids like 2-AG respond to boosts in brain activity by dialing down the release of neurotransmitters from nerve cells.
” Our results deepen the fields understanding of a main seizure-inducing mechanism, with lots of ramifications 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 simply how CBD counters seizures, however more broadly how circuits are balanced in the brain,” included Tsien. “Related imbalances exist in autism and schizophrenia, so the paper may have a more comprehensive effect.”.
Disease-Causing Loop.
The research study results build on how each nerve cell “fires” to send out an electrical pulse down an extension of itself until it reaches a synapse, the space that connects it to the next cell in a neuronal path. When it reaches the cells end prior to the synapse, the pulse sets off the release of compounds called neurotransmitters that float throughout the space to affect the next cell in line. Upon crossing, such signals either encourage the cell to fire (excitation), or use the brakes on shooting (inhibition). Balance in between the 2 are essential to brain function; excessive excitation promotes seizures.
The new research study looked at numerous rodent designs to explore mechanisms behind seizures, typically by determining information-carrying electrical present circulations with fine-tipped electrodes. Other experiments looked at the impact of LPI by genetically eliminating its main signaling partner, or by measuring the release of LPI following seizures.
The tests validated past findings that LPI influences nerve signals by binding to a protein called G-coupled receptor 55 (GPR55), on neuron cell surface areas. This LPI-GPR55 presynaptic interaction was discovered to cause the release of calcium ions within the cell, which encouraged cells to release glutamate, the primary excitatory neurotransmitter.
The research study team discovered that either genetically engineering mice to lack GPR55, or dealing with mice with plant-derived CBD prior to seizure-inducing stimuli, obstructed LPI-mediated effects on both repressive and excitatory synaptic transmission. While previous research studies had implicated GPR55 as a seizure-reducing target of CBD, the existing work offered a more detailed, proposed system 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 offers one process that could explain repeated epileptic seizures, although future studies are needed to validate this.
Even more, the existing research study examined the plant-based cannabinoid CBD, but the authors keep in mind that LPI belongs to a signaling network that includes “endocannabinoids” like 2-Arachidonoylglycerol (2-AG) that occur naturally in human tissues. LPI and 2-AG target receptors are also controlled by CBD, but have various actions at the synapse. While LPI enhances inbound electrical signals, endocannabinoids like 2-AG respond to boosts in brain activity by dialing down the release of neurotransmitters from nerve cells. Remarkably, LPI and 2-AG can be converted into each other through actions of enzymes.
” Theoretically, the brain could manage activity by toggling in between pro-excitatory LPI and the restorative actions of 2-AG,” stated first research study author Evan Rosenberg, PhD, a post-doctoral scholar in the Tseins laboratory. “Drug designers could prevent the enzymes that underpin LPI production or promote its conversion to 2-AG, as an additional approach to control seizures. LPI might likewise serve as a biomarker of seizures or predictor of scientific responsiveness to CBD, supplying an area of future research study.”.
Recommendation: “Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity” by Evan C. Rosenberg, Simon Chamberland, Michael Bazelot, Erica R. Nebet, Xiaohan Wang, Sam McKenzie, Swati Jain, Stuart Greenhill, Max Wilson, Nicole Marley, Alejandro Salah, Shanice Bailey, Pabitra Hriday Patra, Rebecca Rose, Nicolas Chenouard, Simón( e) D. Sun, Drew Jones, György Buzsáki, Orrin Devinsky, Gavin Woodhall, Helen E. Scharfman, Benjamin J. Whalley and Richard W. Tsien, 13 February 2023, Neuron.DOI: 10.1016/ j.neuron.2023.01.018.
In addition to 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. 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), in addition to 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.