(Anderson LL et al. 2017). Sodium channel blockers usually make seizures worse in Dravet syndrome, which can be a confusing concept since we associate problems with the sodium ion channel due to SCN1A mutations leading to overexcitation and, hence, seizures. The key to understanding this apparent contradiction is that SCN1A is mainly expressed in inhibitory interneurons. If the sodium channels do not work properly due to SCN1A mutations, inhibition is impaired and excitation generated in other types of neurons is not properly counteracted. Sodium channel blockers that further suppress this inhibition thus exacerbate seizures in Dravet syndrome.
GS967 is a known sodium channel blocker, so the authors of this study hypothesized that it would worsen seizures in a mouse model with a Dravet-causing SCN1A mutation. Instead, they found that GS967 not only suppressed spontaneous seizures but dramatically decreased the SUDEP rate in a SCN1A+ model. Further investigation showed that GS967 did not affect the action potential of interneurons but did change the firing profile of pyrimidal (excitatory) neurons, which is not found with traditional sodium channel blockers like lamotrigine. When administered over a long time period, the SCN1A+ mice had lower levels of SCN8A – generated ion channels, suggesting there may be some sort of feedback response involved in the mechanism of action. (SCN8A is different from SCN1A and is expressed primarily in pyrimidal excitatory neurons.)
This study was funded in part by a DSF, NIH, Gilead Sciences, and PhRMA.