Murine Study Uncovers Novel Way CBD Reduces Seizures

Researchers of a new murine study have uncovered a novel mechanism in which cannabidiol (CBD) decreases seizures.

Although previous data have shown that CBD reduces seizures across multiple pediatric epilepsy syndromes, the way in which the cannabis component reduces seizures has remained unclear. The current study, which shows that CBD blocked signals carried by the molecule lysophosphatidylinositol (LPI) in neurons, offers new insights into these mechanisms.

Findings published recently in Neuron.¹

“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, PhD, chair of the Department of Physiology and Neuroscience at NYU Langone Health, in a press release. “The study also clarified, not just how CBD counters seizures, but more broadly how circuits are balanced in the brain. Related imbalances are present in autism and schizophrenia, so the paper may have a broader impact.”²

Using multiple murine models, the researchers confirmed previous research on the pro-excitatory impact of LPI, showing that CBD blocks the ability of LPI to amplify nerve signals in the hippocampus by binding to the G-coupled receptor 55 (GPR55) protein, which can promote seizures.

The findings also, for the first time, show that LPI has an impact at the inhibitory synapses, weakening the signals that counter seizures. By engineering the mice to be absent of GPR55 or treating them with plant-derived CBD ahead of seizure-inducing stimuli, the researchers were able to block LPI’s ability of excitatory and inhibitory synaptic transmission.

The findings offer a “loop” theory that nerve signal amplification from LPI weakens the signals that counter seizures, potentially increasing the risk of more seizures, which in turn increases levels of LPI and GPR55.

The signaling network that LPI belongs to also includes 2-arachidonoylglycerol (2-AG) and other endocannibinoids that occur naturally in human tissue, which can be regulated by CBD. However, explained the researchers, they have different actions at the synapse.

“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 postdoctoral scholar in the Tsien lab, in the press release. “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.”

References

1. Rosenberg E, Chamberland S, Bazelot M, et al. Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity. Neuron. Published online February 13, 2023. doi:10.1016/j.neuron.2023.01.018

2. Study reveals how cannabidiol counters epileptic seizures. News release. NYU Langone Health. February 13, 2023. Accessed April 12, 2023. https://nyulangone.org/news/study-reveals-how-cannabidiol-counters-epileptic-seizures