ObjectiveTo investigate the therapeutic effect of proanthocyanidins （PC） on rats with type 2 diabetes mellitus （T2DM） complicated with cognitive impairment （CI） and to explore its potential mechanism by inhibiting the NOD-like receptor family pyrin domain-containing protein 3 （NLRP3）/cysteine-aspartic acid protease-1 （Caspase-1） pathway. MethodsA T2DM rat model was established by high-fat diet combined with intraperitoneal streptozotocin （STZ） injection. Thirty-six diabetic rats complicated with CI were screened by Morris water maze test and randomly divided into model group， PC low-dose （50 mg/kg） group， PC medium-dose （100 mg/kg） group， and PC high-dose （200 mg/kg） group. Another 9 normal rats served as the normal control group. Each group was administered with the corresponding doses of PC or an equal volume of distilled water by gavage for 8 weeks. After the intervention， spatial learning and memory abilities were evaluated using the Morris water maze test. Fasting blood glucose， body weight， and organ coefficients were measured. Pathological changes in the hippocampus were observed by hematoxylin-eosin （HE） staining. Reactive oxygen species （ROS） levels， as well as levels of inflammatory cytokines tumor necrosis factor-α （TNF-α） and interleukin-1β （IL-1β） in hippocampal tissue， were detected by enzyme-linked immunosorbent assay （ELISA）. The protein expression levels of NLRP3， Caspase-1， IL-1β， and IL-18 in the hippocampus were determined by Western blot. ResultsCompared with the normal control group， the model group exhibited significantly increased blood glucose and decreased body weight （P<0.05）. In the Morris water maze test， the model group showed prolonged escape latency， fewer platform crossings， and lower percentages of time and path length in the target quadrant （P<0.05）. Disordered arrangement and pyknotic nuclei were observed in hippocampal neurons. ROS and the levels of TNF-α and IL-1β were elevated， and the protein expression levels of NLRP3， Caspase-1， IL-1β and IL-18 were upregulated （P<0.05）. Compared with the model group， all PC-treated groups， especially the high-dose group， presented dose-dependent improvements in the above indicators， including reduced blood glucose （P<0.05）， improved spatial memory performance in the Morris water maze （P<0.01）， alleviated hippocampal pathological damage， decreased ROS and inflammatory cytokine levels （P<0.05）， and significantly downregulated expression of NLRP3/Caspase-1 pathway-related proteins （P<0.05）. ConclusionProanthocyanidins can ameliorate glycolipid metabolic disorder， visceral organ injury as well as cognitive dysfunction in T2DM rats. The underlying mechanism may be associated with reduced hippocampal ROS levels， inhibition of the NLRP3/Caspase-1 signaling pathway， and attenuated neuroinflammation in the hippocampus， with the optimal effect observed at a dose of 200 mg/kg.