MTRNR2L1/MTRNR2L10 Axis Identified as Protective Regulator, Suppressing Cortical NLRP3 Inflammasome and Neuronal Apoptosis in Experimental Epilepsy

Mechanisms underlying seizure-induced cortical injury in status epilepticus-related experimental epilepsy are not fully understood, particularly regarding upstream regulators of inflammasome activation. The NLRP3 inflammasome is a key mediator of inflammatory responses, and its dysregulation contributes to neurological damage. Current treatments often focus on symptom management, leaving a gap in addressing the fundamental inflammatory and apoptotic pathways driving cortical injury. Clarifying these upstream regulators is crucial for developing targeted neuroprotective strategies.

Researchers combined bioinformatics screening of the GSE134697 dataset with in vivo validation to investigate the MTRNR2L1/MTRNR2L10 axis. Differentially expressed genes (DEGs) were identified using |log2FC|>4 and adjusted P < 0.05. GO/KEGG enrichment analyses and a STRING-based protein-protein interaction (PPI) network prioritized MTRNR2L1/MTRNR2L10. For in vivo validation, 90 SPF SD rats (10 per group) were divided into a basic model module (normal, sham, EP model) and a target-intervention module (negative control, MTRNR2L1 over-expression, MTRNR2L1 knockdown, MTRNR2L10 over-expression, MTRNR2L10 knockdown, and a combined control). Behavioral scoring, histopathology, Western blotting, co-immunoprecipitation, and ELISA were performed to assess outcomes.

Bioinformatics identified 51 DEGs, with MTRNR2L1/MTRNR2L10 uniquely mapping to signal-transduction regulation associated with epilepsy. Cortical expression of MTRNR2L1/MTRNR2L10 in EP rats fell to <30% of control levels. Upregulating this axis significantly lowered Racine seizure scores and neurological deficit scores. This intervention was also associated with reduced NLRP3 inflammasome-related marker expression. Furthermore, it mitigated the loss of BBB-related tight-junction protein markers and reduced cortical neuronal apoptosis. In contrast, silencing either MTRNR2L1 or MTRNR2L10 exacerbated these pathological changes. Co-immunoprecipitation experiments suggested that MTRNR2L1 and MTRNR2L10 are associated within the same protein complex, indicating a coordinated regulatory role.

Upregulating the MTRNR2L1/MTRNR2L10 axis significantly lowered Racine seizure scores and neurological deficit scores, while reducing NLRP3 inflammasome-related marker expression and neuronal apoptosis.