Severe inflammation in C57/BL6 mice leads to prolonged cognitive impairment by initiating the IL-1β/TRPM2 pathway

•Severe inflammation induces prolonged cognitive impairment among C57/BL6 mice.•Prolonged upsurge in hippocampal IL-1β levels exacerbates extended cognitive dysfunction following severe inflammation in C57/BL6 mice.•TRPM2 serves as a mediator of IL-1β’s impact on the persistent cognitive impairment resulting from severe inflammation in C57/BL6.•IL-1β expedites astrocyte apoptosis by upregulating TRPM2 activity. Sepsis could lead to chronic cognitive impairment by unclear molecular mechanisms. Transient receptor potential melastatin-2 (TRPM2) is essential against immunity-related activities and inflammation. Our study attempted to decipher the relationship between cognitive impairment caused by severe inflammation and TRPM2 expression levels. Severe inflammation was induced by intraperitoneally injecting C57/BL6 mice with a high dosage (5 mg kg−1) of Lipopolysaccharide (LPS). Fear conditioning and a Morris water maze test were performed to examine the cognitive abilities of the mice. Moreover, the signaling and expression of pro-inflammatory cytokines and TRPM2 were measured using Western blotting and Reverse transcription-polymerase chain reaction (RT-PCR). Flow cytometry and immunofluorescence staining helped to determine the astrocyte apoptosis rate. Severe inflammation can lead to long-term cognitive impairment in C57/BL6 mice. The interleukin-1 beta (IL-1β) levels intra-hippocampus were significantly elevated until P14 post-LPS introduction. At both P7 and P14, there is an up-regulation of TRPM2 expression within hippocampus. Administration of recombinant IL-1β to astrocytes results in a significant up-regulation of TRPM2 expression. IL-1β or TRPM2 level knockdown helped counter the cognitive impairment caused by significant inflammation. A continuous increase in IL-1β levels within the hippocampus can lead to cognitive impairment by enhancing TRPM2 levels caused by severe inflammation.