The proposed mechanisms of action of CBD in epilepsy

Cannabidiol (CBD) has demonstrated positive effects against a wide spectrum of seizures. In fact, highly purified CBD has been approved in the US and Europe as a medication with good efficacy and safety for treatment of Lennox-Gastaut and Dravet syndromes. An accumulating body of research has suggested three main mechanisms for this antiepileptic effect of CBD: modulation of neuronal Ca2+ mobilization via the GPR55 receptor, of neuronal Ca2+ influx via the TRPV1 receptor, and of adenosine-mediated signaling.

GPR55 is a cell surface receptor that regulates how excitable neurons are – or how often and easy neurons fire. Its activity is thought to be part of the cause for epilepsy because of several evidence: First, its expression is increased in the epileptic hippocampus. Second, in rat models of epilepsy, activation of GPR55 increases the frequency of excitatory postsynaptic currents (EPSC) in the hippocampus, the magnitude of which is significantly greater in epileptic than non-epileptic rats. CBD inhibits the GPR55-mediated increase in EPSC frequency in both non-epileptic and epileptic conditions. This is proposed as a potential mechanism through which CBD alleviates seizure.

TRPV1 is another cell surface receptor with wide expression throughout the central nervous system and peripheral afferent nerve fibre, and an increased expression in epileptic patients’ brains. It promotes neuronal depolarization, increasing their firing rate and synaptic activity; thus, it facilitates seizures. Surprisingly, CBD is found to be a very effective activator of this receptor; however, by activating and rapidly desensitizing TRPV1 receptors at a low concentration, CBD ultimately makes it harder to induce seizures. This is a second potential mode of CBD’s anticonvulsant action.

Adenosine has been described as the endogenous modulator of neuronal excitability, and the brain’s endogenous anticonvulsant and neuroprotectant. CBD increases extracellular adenosine as exemplified by the effects observed in the rat nucleus accumbens for two hours post intrahippocampal injection. Furthermore, CBD inhibits adenosine uptake into macrophages and microglia. In short, a component of CBD’s mechanism of action in seizure control is enhancement of adenosine-mediated signaling through increased availability of extracellular adenosine.

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