TRPM7 contributes to pyroptosis and its involvement in status epilepticus.

Abstract

Background: Pyroptosis, a novel form of programmed cell death, has been implicated in neurodegeneration diseases. However, its role in status epilepticus (SE)-a condition characterized by prolonged or repeated seizures-remains inadequately understood.

Methods: SE were induced by intraperitoneal injection of pilocarpine (PILO). Neuronal excitability was assessed through electroencephalogram (EEG) recordings and patch clamp. Chromatin immunoprecipitation (ChIP) assay was applied to verify the interaction of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) protein with the promoters of Nlrp3 (the gene encoding NOD-like receptor family pyrin domain containing 3) and Trpm7 (transient receptor potential melastatin 7). To further investigate the role of TRPM7 in SE, AAV-sh-TRPM7-EGFP transfected mice and TRPM7 conditional knockout (TRPM7-CKO) mice were utilized.

Results: Our findings revealed elevated levels of IL-18 and IL-1β levels in primary epilepsy patients, along with increased expression level of the TRPM7 in SE models. Knockdown of TRPM7 alleviated neuronal damage and pyroptosis, reversing PILO-treated neuronal hyperexcitability. We demonstrated that p-STAT3 binds to the promoters of both Trpm7 and Nlrp3, modulating their transcriptions in SE. Importantly, inhibition of TRPM7 with NS8593, and inflammasome inhibition with MCC950, alleviated neuronal hyperexcitability and pyroptosis in SE. A new compound, SDUY-225, formulated based on the structure of NS8593 mitigated neuronal damage, pyroptosis, and hyperexcitability.

Conclusions: TRPM7 contributes to pyroptosis in SE, establishing a positive feedback loop involving the p-STAT3/TRPM7/Zn²⁺/p-STAT3 signaling pathway. Findings in this study raise the possibility that targeting TRPM7 and NLRP3 represents a promising therapeutic approach for SE.