PTP1B Inhibitor Claramine Rescues Diabetes-Induced Spatial Learning and Memory Impairment in Mice.

Abstract

Accumulating clinical and epidemiological studies indicate that learning and memory impairment is more prevalent among people with diabetes mellitus (DM). PTP1B is a member of protein tyrosine phosphatase family and participates in a variety of pathophysiological effects including inflammatory, insulin signaling pathway, and learning and memory. This study was aimed to investigate the effects of CA, a specific inhibitor of PTP1B, on spatial learning and memory impairment in diabetic mice caused by high-fat diet and injection of streptozotocin. We found that the protein expressions of PTP1B increased in hippocampal CA1, CA3, and PFC regions of diabetic mice. Network pharmacology results showed that PTP1B might be one of the key targets between diabetes and cognitive dysfunction, and CA might alleviate DM-induced cognitive dysfunction. Animal experiments showed that CA ameliorated DM-induced spatial learning and memory impairment, and improved glucose and lipid metabolic disorders. Moreover, administration of CA alleviated hippocampal structure damage and enhanced the expressions of synaptic proteins, including PSD-95, SYN-1, and SYP in diabetic mice. Furthermore, CA treatment not only significantly down-regulated the expressions of PTP1B and NLRP3 inflammatory related proteins (NLRP3, ASC, Caspase-1, COX-2, IL-1β, and TNF-α), but also significantly up-regulated the expressions of insulin signaling pathway-related proteins (p-IRS1, p-PI3K, p-AKT, and p-GSK-3β) in diabetic mice. Taken together, these results suggested that PTP1B might be a targeted strategy to rescue learning and memory deficits in DM, possibly through inhibition of NLRP3 inflammasome and regulation of insulin signaling pathway.