NLRP3 Inhibitor Alleviates Glycemic Variability-Induced Cognitive Impairment in Aged Rats with Type 2 Diabetes Mellitus

Glycemic variability (GV) markedly exacerbates cognitive impairment in elderly patients with type 2 diabetes mellitus (T2DM), in part through chronic inflammation. This study investigated the therapeutic efficacy of the NLRP3 inflammasome inhibitor MCC950 in mitigating GV-induced cognitive impairment in an aged rat model of T2DM. Aged Sprague-Dawley rats with induced T2DM were subjected to GV conditions, and the effects of MCC950 were evaluated through measurements of body weight, blood glucose, lipid profiles, insulin levels, inflammatory markers, and cognitive function. Transcriptomic analysis was performed on the hippocampus and prefrontal cortex. Treatment with MCC950 significantly alleviated weight loss and hyperglycemia in the GV group compared to untreated GV controls. MCC950 also reduced cholesterol, triglycerides, and the levels of pro-inflammatory markers (interleukin-1beta (IL-1beta) and interleukin-18 (IL-18)). Most notably, MCC950 improved spatial learning and memory retention in the GV group. Immunohistochemical analysis showed a reduction in inflammasome activation and an increase in the expression of the neuronal marker NeuN in the hippocampus. Transcriptomic analysis revealed that MCC950 altered neuroactive ligand-receptor interaction pathways in the hippocampus and influenced receptor binding and cell adhesion processes in the prefrontal cortex. These findings validated the efficacy of NLRP3 inhibitors in mitigating GV-induced cognitive impairment in elderly rats with T2DM and pave the basis for subsequent clinical studies exploring the wider utility of NLRP3-targeted interventions in addressing diabetes-associated cognitive impairment.