Research Reveals Epileptic Seizures Countered By CBD

Cannabidiol (CBD), a component of cannabis, has been shown in research to lessen epileptic seizures in several types of pediatric epilepsy that are resistant to treatment. The current study, headed by investigators at NYU Grossman School of Medicine, discovered that CBD interfered with signals transmitted by a chemical known as lysophosphatidylinositol (LPI). LPI, which is present in brain cells known as neurons, is believed to enhance nerve signals as part of normal function but can be taken over by disease to encourage seizures.

The research, which was published online on February 13 in Neuron, supported earlier findings that CBD prevents LPI from amplifying neuronal signals in the hippocampus, a part of the brain. The new research makes the first argument that LPI also weakens seizure-resistive signals. 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 epileptic 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.”

Epileptic Seizures Triggering Loop

The findings of the study are based on how each neuron “fires,” sending an electrical pulse along an extension of itself until it reaches a synapse, the space that joins it to the following neuron in a neural pathway. The pulse causes the release of substances known as neurotransmitters that float over the synapse and affect the following cell in line when it reaches the end of the cell before the synapse. Such signals either excite the cell to fire (excitation) or put the brakes on firing when they cross (inhibition). To function properly, there must be a balance between the two; excessive excitement can lead to epileptic seizures.

The most common method used in the new study to examine the mechanisms underlying seizures was to use fine-tipped electrodes to measure information-carrying electrical current flows in mouse models. Other studies examined the impact of LPI by genetically eliminating its primary signaling partner or by observing the amount of LPI released after seizures.

The investigations supported earlier results that LPI modifies nerve impulses by attaching to the G-coupled receptor 55 (GPR55), a protein found on the surfaces of neuronal cells. It was discovered that this LPI-GPR55 presynaptic association led to the cell’s release of calcium ions, which in turn stimulated the release of glutamate, the primary excitatory neurotransmitter. Additionally, by reducing the amount and appropriate arrangement of proteins required for inhibition, LPI’s activation of GPR55 on the opposing side of the synapse decreased inhibition.

According to the authors, this results in a “dangerous” two-pronged approach to raising excitability. The research team discovered that blocking LPI-mediated effects on both excitatory and inhibitory synaptic transmission by genetically engineering mice to lack GPR55 or by administering CBD extracted from plants to animals before seizure-inducing stimuli. While earlier research had suggested that CBD was a seizure-reducing target of GPR55, the present study offered a more thorough, hypothesized mechanism of action.

According to scientists, CBD prevents a “positive feedback loop” in which LPI-GPR55 signaling is increased by seizures, leading to an increase in LPI and GPR55 levels. One mechanism that might account for recurrent epileptic seizures is the suggested vicious cycle, though further research is required to prove this.

The authors emphasize that although the current study focused on the cannabinoid CBD derived from plants, LPI is a component of a signaling network that also contains “endocannabinoids” like 2-Arachidonoylglycerol (2-AG), which naturally occur in human tissues. Although LPI and 2-AG target receptors are also controlled by CBD, their effects at the synapse are different. Endocannabinoids like 2-AG react to increases in brain activity by reducing the release of neurotransmitters from nerve cells, in contrast to LPI, which amplifies incoming electrical signals. It’s interesting to note that enzymes can change LPI and 2-AG into one another.

“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, Ph.D., a post-doctoral scholar in Tsein’s lab. “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.”

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