Uyioghosa Evbayiro

 Introduction. Approximately 65 million people in the United States are affected by epilepsy¹.  70% of epileptic conditions are controlled by anti-epileptic drugs (AEDs), and 30% of epileptic conditions such as Dravet Syndrome are refractory to AEDs^2,3. Epilepsy develops from abnormal neuronal connections driven by ion channel mutations, or disturbances in neuronal networks. Mutations in the SCN1A gene encoding neuronal voltage-gated sodium channel (VGSC) Nav 1.1 results in generalized epilepsy and Dravet Syndrome³. Mutations in the SCN8A gene encoding neuronal VGSC channel Nav 1.6 presents with severe infantile encephalopathy³. Clinical trials have demonstrated a significant reduction in the frequency of seizures among Dravet Syndrome patients treated with cannabidiol⁴. Animal models of Dravet Syndrome demonstrate that activators of Nav1.1 and Inhibitors of Nav1.6 significantly reduce seizure activity⁵. These findings indicate that activity at Nav1.1 or Nav1.6 channels may mediate cannabidiol’s antiepileptic effects. Methods. Whole-cell clamp recordings of neuronal-glial cultures with mutant human Nav1.1 and Nav1.6 channels were measured following administration of cannabidiol. Hippocampal slices from SCN1A mutant mice were bathed with cannabidiol with Inhibitory postsynaptic currents (IPSC) and excitatory postsynaptic currents (EPSC) recorded. These procedures were done to identify cannabidiol’s action against abnormal neuronal currents generated by mutant Nav1.1 and Nav1.6 ion channels. Voltage clamp electrophysiology was used to identify cannabidiol effects on Nav channels 1.1 – 1.7. This was done to determine cannabidiol selectivity for different Nav channel subtypes. Results. Cannabidiol had no significant effect on ion currents generated in Nav1.1, but significantly inhibited Nav1.6 peak resurgent current (p<0.01 unpaired test)³. Treatment with cannabidiol increased the frequency of SCN1A mutant mice GABA_A IPSC, and reduced EPSC in excitatory neurons. Increased frequency of GABA_A IPSC was attributed to cannabidiol antagonism at GPR55 with inhibition of EPSC in excitatory neurons mediated by cannabidiol Nav1.6 inhibition⁶. These results indicate VGSC modulation as a mechanism for cannabidiol antiepileptic effects, with selective inhibition of currents generated by mutant Nav1.6. Cannabidiol demonstrates inhibition across Nav channels (Nav1.1 – 1.7) with a hill steep slope >2 across all subtypes⁷. This inhibition of Nav channels across all subtypes indicates cannabidiol inhibition of Nav channels is non-selective. Conclusions. Clinical trials have demonstrated a significant reduction in seizure activity following administration of cannabidiol in refractory epilepsies such as Dravet syndrome. The mechanism behind this reduction of seizure activity is the modulation of VGSCs, notably Nav1.6. Further research is needed to understand cannabidiol’s antiepileptic effects despite its non-selective interaction at multiple Nav channels.

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