Study finds cannabidiol (CBD) reduces seizures in many 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 believed to amplify nerve signals as part of normal function, but can be hijacked by disease to promote seizures.
Published online February 13 in the journal Neuron, this work confirms an earlier finding that CBD blocks the ability of LPI to amplify nerve signals in a region of the brain called the hippocampus. The current findings support for the first time that LPI also weakens signals that oppose seizures, further explaining the value of CBD treatment.
Our results deepen the understanding of a central mechanism of seizure induction, with many implications for the search for new therapeutic approaches. Richard W. Tsien, PhD, corresponding author, chair of the Department of Physiology and Neuroscience at NYU Langone Health.
“The study also clarified not only how the CBD counteracts seizures, but more broadly how circuits are balanced in the brain,” adds Dr. Tsien, also director of NYU Langone's Institute of Neuroscience. "Related imbalances are present in autism and schizophrenia, so the paper may have broader impact."
A pathogenic loop
The study's findings are based on how each neuron 'pulls' to send an electrical impulse along an extension of itself until it reaches a synapse, the space that connects it. to the next cell in a neural pathway. When it reaches the end of the cell before the synapse, the impulse triggers the release of compounds called neurotransmitters which cross the gap to affect the next cell. Once crossed, these signals encourage the cell to activate (excitation) or slow it down (inhibition). The balance between the two is essential to brain function; too much excitement promotes seizures.
The new study looked at several rodent models to explore the mechanisms behind seizures, often by measuring information-carrying electrical current flows using fine-tipped electrodes. Other experiments have looked at the effect of LPI by genetically suppressing its main signaling partner, or by measuring the release of LPI after seizures.
The tests confirmed previous findings that LPI influences nerve signals by binding to a protein called G-coupled receptor 55 (GPR55) on the cell surface of neurons. This presynaptic LPI-GPR55 interaction has been found to cause the release of calcium ions into the cell, which encourages the cells to release glutamate, the main excitatory neurotransmitter.
Additionally, when LPI activated GPR55 on the other side of the synapse, it weakened inhibition, decreasing the supply and proper disposition of proteins necessary for inhibition. Collectively, this creates a "dangerous" two-pronged mechanism for increasing excitability, the authors explain.
The research team found that genetically engineering mice lacking GPR55, or treating mice with plant-derived CBD before seizure-inducing stimuli, blocked LPI-mediated effects on excitatory synaptic transmission and inhibitory. While previous studies have implicated GPR55 as a target of CBD for seizure reduction, current work has proposed a more detailed mechanism of action.
The authors propose that CBD blocks a "positive feedback loop" in which seizures increase LPI-GPR55 signaling, which likely encourages further seizures, which in turn increase LPI and GPR55 levels. The proposed vicious circle constitutes a process that could explain repeated epileptic seizures, although future studies are needed to confirm this.
Additionally, the current study focuses on the plant-derived cannabinoid CBD, but the authors note that LPI is part of a signaling network that includes "endocannabinoids" like 2-Arachidonoylglycerol (2-AG), present 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 reducing the release of neurotransmitters from nerve cells. Interestingly, LPI and 2-AG can be converted into each other by the action of enzymes.
"Theoretically, the brain could control activity by switching between pro-excitatory LPI and the restorative actions of 2-AG," says study first author Evan Rosenberg, PhD, a postdoctoral researcher in Tsien's lab. . “Drug designers could inhibit the enzymes that underlie the production of LPI or promote its conversion to 2-AG, as an additional approach to controlling seizures. IPL could also serve as a biomarker of seizures or a predictor of clinical response to CBD, which is an area for future research. »
Besides Dr. Tsien and Dr. Rosenberg, study authors from the Department of Neuroscience and Physiology and Neuroscience Institute at NYU Langone were Simon Chamberland, Erica Nebet, Xiaohan Wang, Sam McKenzie, Alejandro Salah, Nicolas Chenouard, Simon Sun and György Buzsaki, MD, PhD. Also contributing authors from NYU Langone were Orrin Devinsky, MD, from the Department of Neurology, Rebecca Rose from the Division of Advanced Research Technologies, and Drew R. Jones, PhD, from the Department of Biochemistry and Molecular Pharmacology.