Iguratimod attenuates diabetic cognitive impairment via suppressing B cell activation and CD8⁺ T cell cytotoxicity

Diabetes-induced cognitive impairment (DCI) is a common complication in diabetic patients with an unclear pathogenesis, and there are currently no approved therapeutic drugs available. Iguratimod (IGU) is a novel small molecule immunosuppressant used to treat rheumatoid arthritis. Given the emerging evidence that immune responses mediate cognitive impairment, our study is the first to explore the effects of IGU on cognitive function in DCI mice and the underlying mechanisms. After the establishment of the DCI mouse model, IGU was given by gavage once a day for 8 weeks. Our results show that IGU significantly improves cognitive function in DCI mice and has neuroprotective effects. Further analysis showed that IGU maintained cellular homeostasis in the brain of DCI mice, in particular, it reduced the proportion of B and CD8 T lymphocytes, and significantly inhibited the activation of infiltrating B cells and the expression of cytotoxic factors in CD8 T cells in the brain of DCI mice. In addition, IGU also significantly inhibited B cell activation and CD8 T cell cytotoxicity in the peripheral blood of mice. In our clinical cohort, peripheral Siglec-G⁺ B cells were increased in DCI and showed a non-significant but negative association with cognitive function, in line with the concept that immune activation underlies cognitive deficits. Overall, IGU effectively ameliorates the cognitive function of DCI mice by inhibiting B cell activation and CD8 T cell cytotoxicity, which may be a potential alternative drug for the treatment of DCI.