Over the last 20 years, the use of cannabidiol (CBD) to treat epileptic seizures has gained traction, particularly where anti-seizure medications have failed. CBD’s anticonvulsant properties are well-known; however, a new study has highlighted a previously unknown way CBD reduces seizures, especially in people with treatment-resistant epilepsy.
In very basic physiological terms, electrical impulses travel down a neuronal pathway until they reach a gap, or synapse. Here, neurotransmitters are released and traverse the gap, either exciting or inhibiting the next cell in line.
To function properly, neuronal circuits require coordination between synaptic excitation and inhibition. Dysfunction in the excitatory-inhibitory (E:I) ratio can result in seizures. While it is known that G-protein-coupled receptor 55 (GPR55), present on the surface of neuronal cells, regulates the E:I ratio, the exact mechanism by which it does so is not well understood.
Likewise, how CBD, the non-euphoric component of cannabis, suppresses seizure activity at a molecular level is poorly understood. It is thought that CBD acts as an antagonist, blocking the effects of the lipid lysophosphatidylinositol (LPI), a naturally occurring GPR55 agonist.
Previous double-blind, placebo-controlled phase III clinical trials undertaken in the US have demonstrated that CBD reduces spontaneous recurrent seizures and regulates the E:I ratio in acute seizures. The efficacy of these trials has led the FDA to approve a plant-derived, purified form of CBD to treat seizure disorders.
A study led by researchers at NYU Grossman School of Medicine used rodents to test the relationship between LPI and GPR55 as a potential modulator of E:I ratio and the impact that CBD has on both.
Researchers confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in the hippocampus, the area of the brain associated with epilepsy.
But they also discovered something previously unknown: when LPI interacts with GPR55, it weakens the signals that suppress seizures. This means that the LPI-GPR55 pathway can result in a positive feedback loop whereby seizures increase LPI-GPR55 signaling, producing more seizures and increasing levels of LPI-GPR55. The process continues in a vicious cycle, providing one explanation for prolonged seizure activity.
Findings suggest that CBD effectively short-circuits this feedback loop, restoring the E:I ratio, thereby further increasing CBD's value as an anticonvulsant 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 Richard Tsien, chair of the Department of Physiology and Neuroscience at NYU Langone Health and corresponding author of the study.
Given that E:I imbalances are found in other conditions, the findings of this study have the potential for wider application.
“The study also clarified, not just how CBD counters seizures, but more broadly how circuits are balanced in the brain,” Tsien said. “Related imbalances are present in autism and schizophrenia, so the paper may have a broader impact.”
The new study was published in Neuron.
Source: NYU Langone Health via EurekAlert!
