Abstract
Background: Sarsasapogenin (Sar), a natural steroidal compound, shows neuroprotective, promoting cognition, anti-inflammatory, anti-thrombosis effects, etc. However, whether Sar can ameliorate diabetes-associated cognitive impairment and whether it is related to the anti-inflammatory and anti-thrombosis effects of Sar, it remains unknown. Methods: Streptozotocin-induced diabetic rats were treated orally with Sar (20 and 60 mg/kg), and normal rats was orally administrated of Sar (60 mg/kg). Cognitive tests were performed using Morris water maze. Nucleotide-binding domain and leucine-rich repeat containing protein 1 (NLRP1) inflammasome (NLRP1, cleaved caspase 1, IL-1β, and IL-18), as well as thrombin and its receptor protease-activated receptor 1 (PAR-1) pathway and advanced glycation endproducts (AGEs) and its receptor RAGE axis were examined in the brain of diabetic rats. Meanwhile high glucose-cultured human SH-SY5Y cells were used to further investigate the effects of Sar (0.2, 1, 5 μM) on central neurons and deeply explore the mechanism. Results: Sar markedly increased numbers of crossing platform and percentage of time spent in the target quadrant in Morris water maze tests in diabetic rats, accompanied by inhibitions of NLRP1 inflammasome, PAR-1 upregulation, and AGEs/RAGE axis in cerebral cortex. Moreover, Sar mitigated neuronal damages, NLRP1 inflammasome activation, and PAR-1 upregulation in high glucose-cultured SH-SY5Y cells, and the effects were similar to those of the PAR-1 inhibition with a selective PAR-1 antagonist vorapaxar. But Sar also did not affect thrombin activity in the brain of diabetic rats and high glucose-cultured SH-SY5Y cells. Further studies indicated that the key molecules of NLRP1 inflammasome and the phosphorylated NF-kappaB p65 were remarkably decreased in SH-SY5Y cells cultured with high glucose after PAR-1 knockdown by using F2R (the gene symbol of PAR-1) shRNA, and these effects were confirmed by using Sar addition in such condition. Conclusions: These findings demonstrated that Sar could improve memory impairment caused by diabetes, which was achieved through suppressing neuroinflammation from the activated NLRP1 inflammasome and NF-kappaB mediated by thrombin/PAR-1 activation in brain. Moreover, Sar was proved to be a pleiotropic neuroprotective agent and memory enhancer.
Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-kappaB pathway and downstream enzymes involved in prostaglandin biosynthesis