Spatial learning and memory are impaired in diabetic animals. The interaction of advanced glycation end products (AGEs) with the receptor of AGEs (RAGE), resulting in the activation of nuclear factor-κB (NF-κB), plays an important role in pathways leading to the cytotoxic effects to neurons. Danshensu, a compound from Salvia miltiorrhiza Bunge, has neuroprotective effects. This study aimed to investigate the role of AGE-mediated neuroinflammation in learning and memory deficits and the effect of Danshensu on the cognitive decline in diabetic mice. C57BL/6 mice were injected intraperitoneally with streptozotocin. Sodium Danshensu (sodium salt of Danshensu) was administered at a dose of 15, 30, or 60 mg/kg for 12 weeks. The results showed that diabetes caused impairment in acquisition and retrieval processes, as demonstrated by performance in the Morris water maze test. Danshensu not only reduced the mean escape latency but also increased the percentage of time spent in the target quadrant. Western blot analysis revealed that there was a significant increase in the expression of RAGE, p-p38, and COX-2, and the NF-κB activation. Danshensu partly blocked the expression of RAGE, p-p38, and COX-2, and NF-κB activation, and inhibited the increase of TNF-α, IL-6, and PGE₂. However, Danshensu did not affect body weight and the levels of blood glucose, glycosylated hemoglobin, insulin, and AGEs. These findings demonstrate that AGE-mediated neuroinflammation plays an important role in learning and memory deficits in diabetic mice and that Danshensu may provide a potential alternative for the prevention of cognitive impairment associated with diabetes by attenuating AGE-mediated neuroinflammation.
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