Neuroinflammation promotes the development of pharmacoresistant epilepsy by triggering the MSK1/CREB signaling pathway.

Epilepsy affects about 1% of the global population, with 30% of patients developing pharmacoresistant epilepsy (PRE). The underlying causes of PRE remain elusive. However, there is suspicion that neuroinflammation may cause recurrent epilepsy by activating the mitogen and stress-activated protein kinase 1 (MSK1)/cAMP response element-binding protein (CREB) signaling pathway. Our study integrates clinical, cellular, and animal research to explore this link. We found that MSK1 and CREB expression significantly increased in epileptic patients and model rats after seizures, with interactions observed both in vivo and in vitro. Inflammatory factors correlated with epilepsy in both patient and rat populations, showing a significant increase in neuroinflammatory markers in those with PRE. However, MSK1 intervention had limited effects on neuroinflammatory factor expression. Interestingly, inflammation activates the MSK1/CREB pathway in rat hippocampal neurons, suggesting that neuroinflammation promotes seizure and PRE formation via MSK1-mediated CREB activation. Our study highlights the potential of targeting the MSK1/CREB pathway to develop novel therapeutic approaches for PRE, offering hope for improved clinical outcomes in epilepsy management.