Blocking salt‐inducible kinases with YKL‐06‐061 prevents PTZ‐induced seizures in mice

Introduction Epilepsy is one of the most common neurological diseases, while over one third of adults with epilepsy still have inadequate seizure control. Although mutations in salt‐inducible kinases (SIKs) have been identified in epileptic encephalopathy, it is not known whether blocking SIKs can prevent pentylenetetrazole (PTZ)‐induced seizures. Methods We first determined the time course of SIKs (including SIK 1, 2, and 3) in the hippocampus of PTZ treated mice. And then, we evaluated the effects of anti‐epilepsy drug valproate acid (VPA) on the expression of SIK 1, 2, and 3 in the hippocampus of PTZ treated mice. Next, we investigated the effect of different dose of SIKs inhibitor YKL‐06‐061 on the epileptic seizures and neuronal activation by determining the expression of immediate early genes (IEGs) in the PTZ treated mice. Results We found that PTZ selectively induced enhanced expression of SIK1 in the hippocampus, which was blocked by VPA treatment. Notably, YKL‐06‐061 decreased seizure activity and prevented neuronal overactivity, as indicated by the reduced expression of IEGs in the hippocampus and prefrontal cortex. Conclusion Our findings provide the first evidence that SIK1 affects gene regulation in neuronal hyperactivity, which is involved in seizure behavior. Targeting SIK1 through the development of selective inhibitors may lead to disease‐modifying therapies that reduce epilepsy progression. A schematic illustration of the proposed mechanism for YKL‐06‐061 prevents PTZ‐induced seizures in mice. PTZ induces high expression of SIK1, leading IEGs overexpression and appearing seizure behavior in mice. SIKs inhibitors (YKL‐06‐061) reduce the expression of IEGs, thereby improving epilepsy of mice.